Tricyclic compounds as anticancer agents

ABSTRACT

The present invention is directed to tricyclic compounds, pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

This application claims priority from U.S. Provisional Application No.61/920,500 filed Dec. 24, 2013, the disclosures of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention provides novel tricyclic compounds, pharmaceuticalcompositions comprising the compounds, and methods of using them, forexample, for the treatment or prophylaxis of certain cancers and totheir use in therapy.

BACKGROUND OF THE INVENTION

The genomes of eukaryotic organisms are highly organized within thenucleus of the cell. The long strands of duplex DNA are wrapped aroundan octomer of histone proteins to form a nucleosome. This basic unit isthen further compressed by the aggregation and folding of nucleosomes toform a highly condensed chromatin structure. A range of different statesof condensation are possible, and the tightness of this structure variesduring the cell cycle, being most compact during the process of celldivision. There has been appreciation recently that chromatin templatesform a fundamentally important set of gene control mechanisms referredto as epigenetic regulation. By conferring a wide range of specificchemical modifications to histones and DNA (such as acetylation,methylation, phosphorylation, ubiquitinylation and SUMOylation)epigenetic regulators modulate the structure, function and accessibilityof our genome, thereby exerting a huge impact in gene expression.

Histone acetylation is most usually associated with the activation ofgene transcription, as the modification loosens the interaction of theDNA and the histone octomer by changing the electrostatics. In additionto this physical change, specific proteins bind to acetylated lysineresidues within histones to read the epigenetic code. Bromodomains aresmall (˜110 amino acid) distinct domains within proteins that bind toacetylated lysine residues commonly but not exclusively in the contextof histones. There is a family of around 50 proteins known to containbromodomains, and they have a range of functions within the cell. TheBET family of bromodomain containing proteins comprises 4 proteins(BRD2, BRD3, BRD4 and BRD-T) which contain tandem bromodomains capableof binding to two acetylated lysine residues in close proximity,increasing the specificity of the interaction.

BRD2 and BRD3 are reported to associate with histones along activelytranscribed genes and may be involved in facilitating transcriptionalelongation (Leroy et al., Mol. Cell. 2008 30(1):51-60), while BRD4appears to be involved in the recruitment of the pTEF-I3 complex toinducible genes, resulting in phosphorylation of RNA polymerase andincreased transcriptional output (Hargreaves et al., Cell, 2009 138(1):1294145). All family members have been reported to have some function incontrolling or executing aspects of the cell cycle, and have been shownto remain in complex with chromosomes during cell division—suggesting arole in the maintenance of epigenetic memory. In addition some virusesmake use of these proteins to tether their genomes to the host cellchromatin, as part of the process of viral replication (You et al.,Cell, 2004 117(3):349-60).

Recent articles relating to this target include Prinjha et al., Trendsin Pharmacological Sciences, March 2012, Vol. 33, No. 3, pp. 146-153;Conway, ACS Med. Chem. Lett., 2012, 3, 691-694 and Hewings et al., J.Med. Chem., 2012, 55, 9393-9413.

Small molecule BET inhibitors that are reported to be in developmentinclude GSK-525762A, OTX-015, TEN-010 as well as others from theUniversity of Oxford and Constellation Pharmaceuticals Inc.

Hundreds of epigenetic effectors have been identified, many of which arechromatin-binding proteins or chromatin-modifying enzymes. Theseproteins have been associated with a variety of disorders such asneurodegenerative disorders, metabolic diseases, inflammation andcancer. Thus, these compounds which inhibit the binding of a bromodomainwith its cognate acetylated proteins, promise new approaches in thetreatment of a range of autoimmune and inflammatory diseases orconditions and in the treatment of various types of cancer.

SUMMARY OF THE INVENTION

There is provided a compound of formula (I)

wherein:

A is optionally substituted heterocyclo or optionally substitutedheteroaryl, wherein the substituents are one or more R;

R is independently one or more hydrogen, CD₃, halogen, haloalkyl,hydroxyalkyl, CN, CF₃, CH₂F, CHF₂, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₆)cycloalkyl, optionally substituted heterocyclo, —OR⁴, —CONR³R⁴,—NR³R⁴, NR³R⁴(C₁-C₆)alkyl-, —NR⁶OCOR³, —NR⁶COR³, NR⁶COR³(C₁-C₆)alkyl-,—NR⁶CO₂R³, NR⁶CO₂R³(C₁-C₆)alkyl-, —NR⁶CONR³R⁴, —SO₂NR³R⁴,SO₂(C₁-C₆)alkyl-, —NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴ or NR⁶SO₂R⁴(C₁-C₆)alkyl-;

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, —CONR³R⁴, —NR⁶COOR⁴, —NR⁶CONR³R⁴,—NR⁶COR⁴, —NR⁶SO₂R⁵, —SO₂NR³R⁴, —NR⁶SO₂NR³R⁴, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted (C₁-C₆) alkoxy, optionally substituted aryl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted aryl-SO₂,optionally substituted heteroaryl or optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring; R⁵ is hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, optionally substituted aryl,optionally substituted aryl(C₁-C₆)alkyl, optionally substitutedaryloxy(C₁-C₆)alkyl, optionally substituted (C₁-C₆)alkyl-SO₂—,optionally substituted heterocyclyl, optionally substitutedheterocyclyl(C₁-C₆)alkyl, optionally substituted heteroaryl oroptionally substituted heteroaryl(C₁-C₆)alkyl;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

R⁷ is hydrogen, optionally substituted (C₁-C₆)alkyl, —OR⁴, CN orhalogen;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In another aspect, there is provided a pharmaceutical compositioncomprising a compound of the invention or a pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable carriers,diluents or excipients.

In another aspect, there is provided a compound of the invention or apharmaceutically acceptable salt thereof for use in therapy. Inparticular, for use in the treatment of a disease or condition for whicha bromodomain inhibitor is indicated.

In another aspect, there is provided a method of treating autoimmune andinflammatory diseases or conditions which comprises administering to asubject in need thereof a therapeutically effective amount of abromodomain inhibitor.

In another aspect, there is provided a method of treating cancer whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a bromodomain inhibitor.

In another aspect of the present invention, there is provided a methodfor treating a bromodomain-containing protein mediated disorder in apatient in need thereof, comprising the step of administering to saidpatient a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect of the present invention, there is provided a compoundof formula (I)

wherein:

A is optionally substituted heterocyclo or optionally substitutedheteroaryl, wherein the substituents are one or more R;

R is independently one or more hydrogen, CD₃, halogen, haloalkyl,hydroxyalkyl, CN, CF₃, CH₂F, CHF₂, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₆)cycloalkyl, optionally substituted heterocyclo, —OR⁴, —CONR³R⁴,—NR³R⁴, NR³R⁴(C₁-C₆)alkyl-, —NR⁶OCOR³, —NR⁶COR³, NR⁶COR³(C₁-C₆)alkyl-,—NR⁶CO₂R³, NR⁶CO₂R³(C₁-C₆)alkyl-, —NR⁶CONR³R⁴, —SO₂NR³R⁴,SO₂(C₁-C₆)alkyl-, —NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴ or NR⁶SO₂R⁴(C₁-C₆)alkyl-;

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, —CONR³R⁴, —NR⁶COOR⁴, —NR⁶CONR³R⁴,—NR⁶COR⁴, —NR⁶SO₂R⁵, —SO₂NR³R⁴, —NR⁶SO₂NR³R⁴, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted (C₁-C₆) alkoxy, optionally substituted aryl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted aryl-SO₂,optionally substituted heteroaryl or optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring;

R⁵ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

R⁷ is hydrogen, optionally substituted (C₁-C₆)alkyl, —OR⁴, CN orhalogen;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In a second aspect of the invention, there is provided a compoundaccording to claim 1 of formula (II)

wherein:

A is optionally substituted heterocyclo or optionally substitutedheteroaryl, wherein the substituents are one or more R;

R is independently one or more hydrogen, CD₃, halogen, haloalkyl,hydroxyalkyl, CN, CF₃, CH₂F, CHF₂, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₆)cycloalkyl, optionally substituted heterocyclo, —OR⁴, —CONR³R⁴,—NR³R⁴, NR³R⁴(C₁-C₆)alkyl-, —NR⁶OCOR³, —NR⁶COR³, NR⁶COR³(C₁-C₆)alkyl-,—NR⁶CO₂R³, NR⁶CO₂R³(C₁-C₆)alkyl-, —NR⁶CONR³R⁴, —SO₂NR³R⁴,SO₂(C₁-C₆)alkyl-, —NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴ or NR⁶SO₂R⁴(C₁-C₆)alkyl-;

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, —CONR³R⁴, —NR⁶COOR⁴, —NR⁶CONR³R⁴,—NR⁶COR⁴, —NR⁶SO₂R⁵, —SO₂NR³R⁴, —NR⁶SO₂NR³R⁴, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted (C₁-C₆) alkoxy, optionally substituted aryl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted aryl-SO₂,optionally substituted heteroaryl or optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring;

R⁵ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

R⁷ is hydrogen, optionally substituted (C₁-C₆)alkyl, —OR⁴, CN orhalogen;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In a third aspect of the invention within the scope of the first twoaspects, there is provided a compound of formula (II)

wherein:

A is optionally substituted heterocyclo or optionally substitutedheteroaryl, wherein the substituents are one or more R;

R is independently one or more hydrogen, CD₃, halogen, haloalkyl,hydroxyalkyl, CN, CF₃, CH₂F, CHF₂, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₆)cycloalkyl, optionally substituted heterocyclo, —OR⁴, —CONR³R⁴,—NR³R⁴, NR³R⁴(C₁-C₆)alkyl-, —NR⁶OCOR³, —NR⁶COR³, NR⁶COR³(C₁-C₆)alkyl-,—NR⁶CO₂R³, NR⁶CO₂R³(C₁-C₆)alkyl-, —NR⁶CONR³R⁴, —SO₂NR³R⁴,SO₂(C₁-C₆)alkyl-, —NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴ or NR⁶SO₂R⁴(C₁-C₆)alkyl-;

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₁-C₆)alkoxy, optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In a 4^(th) aspect within the scope of the prior aspects, there isprovided a compound of the formula

wherein

A is

R is independently one or more hydrogen, CD₃, halogen, haloalkyl,hydroxyalkyl, CN, CF₃, CH₂F, CHF₂, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₆)cycloalkyl, optionally substituted heterocyclo, —OR⁴, —CONR³R⁴,—NR³R⁴, NR³R⁴(C₁-C₆)alkyl-, —NR⁶OCOR³, —NR⁶COR³, NR⁶COR³(C₁-C₆)alkyl-,—NR⁶CO₂R³, NR⁶CO₂R³(C₁-C₆)alkyl-, —NR⁶CONR³R⁴, —SO₂NR³R⁴,SO₂(C₁-C₆)alkyl-, —NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴ or NR⁶SO₂R⁴(C₁-C₆)alkyl-;

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₁-C₆)alkoxy, optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In a 5^(th) aspect of the invention within the scope of the prioraspects, there is provided a compound of the formula

wherein:

A is

R is independently one or more hydrogen, CD₃, halogen, haloalkyl,hydroxyalkyl, CN, CF₃, CH₂F, CHF₂, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₆)cycloalkyl, optionally substituted heterocyclo, —OR⁴, —CONR³R⁴,—NR³R⁴, NR³R⁴(C₁-C₆)alkyl-, —NR⁶OCOR³, —NR⁶COR³, NR⁶COR³(C₁-C₆)alkyl-,—NR⁶CO₂R³, NR⁶CO₂R³(C₁-C₆)alkyl-, —NR⁶CONR³R⁴, —SO₂NR³R⁴,SO₂(C₁-C₆)alkyl-, —NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴ or NR⁶SO₂R⁴(C₁-C₆)alkyl-;

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₁-C₆)alkoxy, optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In a 6^(th) aspect of the invention within the scope of the prioraspects, there is provided a compound of the formula

wherein:

A is

R is independently one or more hydrogen, CD₃, halogen, haloalkyl,hydroxyalkyl, CN, CF₃, CH₂F, CHF₂, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₆)cycloalkyl, optionally substituted heterocyclo, —OR⁴, —CONR³R⁴,—NR³R⁴, NR³R⁴(C₁-C₆)alkyl-, —NR⁶OCOR³, —NR⁶COR³, NR⁶COR³(C₁-C₆)alkyl-,—NR⁶CO₂R³, NR⁶CO₂R³(C₁-C₆)alkyl-, —NR⁶CONR³R⁴, —SO₂NR³R⁴,SO₂(C₁-C₆)alkyl-, —NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴ or NR⁶SO₂R⁴(C₁-C₆)alkyl-;

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₁-C₆)alkoxy, optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In a 7^(th) aspect of the invention within the scope of the prioraspects, there is provided a compound of the formula

wherein:

A is

X and Y are independently selected from hydrogen, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclo;

Z is hydrogen, halogen, —OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NR³R⁴,—CONR³R⁴, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴, —NR⁶SO₂NR³R⁴ or —NR⁶SO₂R⁴;

R¹ is, independently at each occurrence, one or more hydrogen, halogen,—CN, —OR⁴, —NR³R⁴, —CONR³R⁴, —COOH, —OCONR³R⁴, —NR⁶OCOR³, —NR⁶CONR³R⁴,—NR⁶SO₂NR³R⁴, —NR⁶SO₂R⁴, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₁-C₆)alkoxy, optionally substituted(C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl-CO—, optionallysubstituted (C₃-C₈)cycloalkyl-SO₂—, optionally substituted aryl(C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy,optionally substituted heterocyclyl-CO—, optionally substitutedheterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂—,—NR⁶SO₂-optionally substituted (C₁-C₆)alkyl, —NR⁶SO₂-optionallysubstituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NR⁶SO₂— oroptionally substituted heterocyclo-NR⁶SO₂—;

R² is hydrogen, halogen, —CN, OH, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₁-C₆)alkoxy, optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substitutedaryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionallysubstituted (C₁-C₆)alkyl-SO₂—, optionally substituted heterocyclyl,optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substitutedheteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl,

R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which theyare attached to form an optionally substituted (C₄-C₈) heteroaryl or(C₄-C₈) heterocyclic ring;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

In another aspect, there is provided a compound selected from theexemplified examples within the scope of the first aspect, or apharmaceutically acceptable salt, tautomer or stereoisomer thereof.

In another aspect, there is provided a compound selected from any subsetlist of compounds within the scope of any of the above aspects.

In another aspect, there is provided a compound selected from thefollowing

-   2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-(1,1,1,7,7,7-hexafluoroheptan-4-yl)-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1S)-4,4,4-trifluoro-1-phenylbutyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   2-{3-[4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,-   5-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,-   2-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   (1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol,-   2-{3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol-   2-{3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-[3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,-   (1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol,-   2-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   (1S)-1-cyclopropyl-1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,-   (1R)-1-cyclopropyl-1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,-   2-{5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{5-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{8-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   (1R)-1-cyclopropyl-1-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,-   2-{6-fluoro-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{6-chloro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-[(R)-(4,4-difluorocyclohexyl)({9-fluoro-7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine,-   (1S)-1-cyclopropyl-1-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,-   2-{8-fluoro-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{5-[(5-chloropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{5-[(3-chloropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{5-[(4-chloropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{5-[(4,4-difluorocyclohexyl)(3-fluoropyridin-2-yl)methyl]-6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{6-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{3-[4-(²H₃)methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   2-{3-[4-methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,-   5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-methoxy-1-methyl-1H-1,2,3-triazole,-   2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine,-   N-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}acetamide,-   N-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}methanesulfonamide,-   methyl    N-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}carbamate,-   5-{6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,-   5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,-   5-{9-fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,-   5-{6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,-   N-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl]cyclopropanesulfonamide,-   5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,-   5-{9-methanesulfonyl-6,7-dimethoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,    and-   2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

and/or a pharmaceutically acceptable salt, tautomer or stereoisomerthereof.

One embodiment of the invention provides compounds wherein A isoptionally substituted heterocyclo or optionally substituted heteroaryl,wherein the substituents are one or more R;

Another embodiment of the invention provides compounds wherein A is

and R is independently one or more hydrogen, CD₃, OCD₃, CF₃, CHF₂ or(C₁-C₃)alkyl.

Another embodiment of the invention provides compounds wherein A is

and R is independently one or more hydrogen, CD₃, OCD₃, CF₃, CHF₂ or(C₁-C₃)alkyl.

In another embodiment, the compounds of the invention have IC₅₀ values≦250 nM.

In another embodiment, the compounds of the invention have IC₅₀ values≦25 nM

In another embodiment, the compounds of the invention have IC₅₀ values≦5 nM.

OTHER EMBODIMENTS OF THE INVENTION

In another embodiment, the invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of theinvention or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, or a solvate thereof.

In another embodiment, the invention provides a process for making acompound of the invention or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the invention provides a method for inhibitingactivity of a bromodomain-containing protein mediated disorder in apatient in need thereof comprising the step of administering to saidpatient at least one compound of the invention.

In another embodiment, the invention provides a method for the treatmentand/or prophylaxis of various types of cancer, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of one or more compounds of theinvention, alone, or, optionally, in combination with another compoundof the invention and/or at least one other type of therapeutic agent.

In another embodiment, the invention provides a method for the treatmentand/or prophylaxis of various types of cancer, including withoutlimitation, small cell lung cancer, non-small cell lung cancer,colorectal cancer, multiple myeloma, acute myeloid leukemia (AML), acutelymphoblastic leukemia (ALL), pancreatic cancer, liver cancer,hepatocellular cancer, neuroblastoma, other solid tumors or otherhematological cancers.

In another embodiment, the invention provides a method for the treatmentand/or prophylaxis of various types of cancer, including withoutlimitation, small cell lung cancer, non-small cell lung cancer,colorectal cancer, multiple myeloma or AML.

In another embodiment, the invention provides a compound of the presentinvention for use in therapy.

In another embodiment, the invention provides a combined preparation ofa compound of the present invention and additional therapeutic agent(s)for simultaneous, separate or sequential use in therapy.

In another embodiment, the invention provides a method of inhibiting abromodomain-containing protein comprising contacting said protein withany exemplified compound or a pharmaceutically acceptable salt orcomposition thereof.

Therapeutic Applications

The compounds of formula (I) of the invention are bromodomain inhibitorsand have potential utility in the treatment of diseases and conditionsfor which a bromodomain inhibitor is indicated.

In one embodiment there is provided a method for the treatment of adisease or condition, for which a bromodomain inhibitor is indicated, ina subject in need thereof which comprises administering atherapeutically effective amount of compound of formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment there is provided a method for treatment of achronic autoimmune and/or inflammatory condition, in a subject in needthereof which comprises administering a therapeutically effective amountof one or more compounds of formula (I) or a pharmaceutically acceptablesalt thereof.

In a further embodiment there is provided a method for treatment ofcancer in a subject in need thereof which comprises administering atherapeutically effective amount of one or more compounds of formula (I)or a pharmaceutically acceptable salt thereof.

In one embodiment the subject in need thereof is a mammal, particularlya human.

Bromodomain inhibitors are believed to be useful in the treatment of avariety of diseases or conditions related to systemic or tissueinflammation, inflammatory responses to infection or hypoxia, cellularactivation and proliferation, lipid metabolism, fibrosis and in theprevention and treatment of viral infections.

Bromodomain inhibitors may be useful in the treatment of a wide varietyof chronic autoimmune and inflammatory conditions such as rheumatoidarthritis, osteoarthritis, acute gout, psoriasis, systemic lupuserythematosus, multiple sclerosis, inflammatory bowel disease (Crohn'sdisease and Ulcerative colitis), asthma, chronic obstructive airwaysdisease, pneumonitis, myocarditis, pericarditis, myositis, eczema,dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis,vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis,uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis,sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis,type I diabetes and acute rejection of transplanted organs.

Bromodomain inhibitors may be useful in the treatment of a wide varietyof acute inflammatory conditions such as acute gout, giant cellarteritis, nephritis including lupus nephritis, vasculitis with organinvolvement such as glomerulonephritis, vasculitis including giant cellarteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet'sdisease, Kawasaki disease, Takayasu's Arteritis and acute rejection oftransplanted organs.

Bromodomain inhibitors may be useful in the prevention or treatment ofdiseases or conditions which involve inflammatory responses toinfections with bacteria, viruses, fungi, parasites or their toxins,such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemicinflammatory response syndrome (SIRS), multi-organ dysfunction syndrome,toxic shock syndrome, acute lung injury, ARDS (adult respiratorydistress syndrome), acute renal failure, fulminant hepatitis, burns,acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimerreactions, encephalitis, myelitis, meningitis, malaria, SIRS associatedwith viral infections such as influenza, herpes zoster, herpes simplexand coronavirus.

Bromodomain inhibitors may be useful in the prevention or treatment ofconditions associated with ischaemia-reperfusion injury such asmyocardial infarction, cerebrovascular ischaemia (stroke), acutecoronary syndromes, renal reperfusion injury, organ transplantation,coronary artery bypass grafting, cardio-pulmonary bypass procedures andpulmonary, renal, hepatic, gastro-intestinal or peripheral limbembolism.

Bromodomain inhibitors may be useful in the treatment of disorders oflipid metabolism via the regulation of APO-A1 such ashypercholesterolemia, atherosclerosis and Alzheimer's disease.

Bromodomain inhibitors may be useful in the treatment of fibroticconditions such as idiopathic pulmonary fibrosis, renal fibrosis,post-operative stricture, keloid formation, scleroderma and cardiacfibrosis.

Bromodomain inhibitors may be useful in the prevention and treatment ofviral infections such as herpes virus, human papilloma virus,adenovirus, poxvirus and other DNA viruses.

Bromodomain inhibitors may also be useful in the treatment of cancer,including hematological, epithelial including lung, breast and coloncarcinomas, midline carcinomas, mesenchymal, hepatic, renal andneurological tumours.

In one embodiment the disease or condition for which a bromodomaininhibitor is indicated is selected from diseases associated withsystemic inflammatory response syndrome, such as sepsis, burns,pancreatitis, major trauma, hemorrhage and ischemia. In this embodiment,the bromodomain inhibitor would be administered at the point ofdiagnosis to reduce the incidence of SIRS, the onset of shock,multi-organ dysfunction syndrome, which includes the onset of acute lunginjury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injuryand mortality. In another embodiment the bromodomain inhibitor would beadministered prior to surgical or other procedures associated with ahigh risk of sepsis, hemorrhage, extensive tissue damage, SIRS or MODS(multiple organ dysfunction syndrome). In a particular embodiment thedisease or condition for which a bromodomain inhibitor is indicated issepsis, sepsis syndrome, septic shock and endotoxemia. In anotherembodiment, the bromodomain inhibitor is indicated for the treatment ofacute or acute on chronic pancreatitis. In another embodiment thebromodomain inhibitor is indicated for the treatment of burns.

In one embodiment the disease or condition for which a bromodomaininhibitor is indicated is selected from herpes simplex infections andreactivations, cold sores, herpes zoster infections and reactivations,chickenpox, shingles, human papilloma virus, cervical neoplasia,adenovirus infections, including acute respiratory disease, and poxvirusinfections such as cowpox and smallpox and African swine fever virus.

The term “diseases or conditions for which a bromodomain inhibitor isindicated” is intended to include any of or all of the above diseasestates.

In one embodiment, there is provided a method for inhibiting abromodomain which comprises contacting the bromodomain with a compoundof formula (1) or a pharmaceutically acceptable salt thereof.

While it is possible that for use in therapy, a compound of formula (I)as well as pharmaceutically acceptable salts thereof may be administeredas the compound itself, it is more commonly presented as apharmaceutical composition.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient pep unit dose.Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Such unit doses may therefore be administered more than once a day.Preferred unit dosage compositions are those containing a daily dose orsub-dose (for administration more than once a day), as herein aboverecited, or an appropriate fraction thereof, of an active ingredient.

Types of cancers that may be treated with the compounds of thisinvention include, but are not limited to, brain cancers, skin cancers,bladder cancers, ovarian cancers, breast cancers, gastric cancers,pancreatic cancers, prostate cancers, colon cancers, blood cancers, lungcancers and bone cancers. Examples of such cancer types includeneuroblastoma, intestine carcinoma such as rectum carcinoma, coloncarcinoma, familiar adenomatous polyposis carcinoma and hereditarynon-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma,larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary glandcarcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidcarcinoma, papillary thyroid carcinoma, renal carcinoma, kidneyparenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterinecorpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreaticcarcinoma, prostate carcinoma, testis carcinoma, breast carcinoma,urinary carcinoma, melanoma, brain tumors such as glioblastoma,astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermaltumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acutelymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cellleukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellularcarcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lungcarcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma,teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma,craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma,liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma.

In addition to apoptosis defects found in tumors, defects in the abilityto eliminate self-reactive cells of the immune system due to apoptosisresistance are considered to play a key role in the pathogenesis ofautoimmune diseases. Autoimmune diseases are characterized in that thecells of the immune system produce antibodies against its own organs andmolecules or directly attack tissues resulting in the destruction of thelatter. A failure of those self-reactive cells to undergo apoptosisleads to the manifestation of the disease. Defects in apoptosisregulation have been identified in autoimmune diseases such as systemiclupus erythematosus or rheumatoid arthritis.

Thus, according to another embodiment, the invention provides a methodof treating an autoimmune disease by providing to a patient in needthereof a compound or composition of the present invention. Examples ofsuch autoimmune diseases include, but are not limited to, collagendiseases such as rheumatoid arthritis, systemic lupus erythematosus.Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome,esophageal dysmotility, telangiectasia), dermatomyositis, vasculitis(Morbus Wegener's) and Sjogren's syndrome, renal diseases such asGoodpasture's syndrome, rapidly-progressing glomerulonephritis andmembrano-proliferative glomerulonephritis type II, endocrine diseasessuch as type-I diabetes, autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmuneparathyroidism, pernicious anemia, gonad insufficiency, idiopathicMorbus Addison's, hyperthyreosis, Hashimoto's thyroiditis and primarymyxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid,herpes gestationis, epidermolysis bullosa and erythema multiforme major,liver diseases such as primary biliary cirrhosis, autoimmunecholangitis, autoimmune hepatitis type-1, autoimmune hepatitis type-2,primary sclerosing cholangitis, neuronal diseases such as multiplesclerosis, myasthenia gravis, myasthenic Lambert-Eaton syndrome,acquired neuromyotomy, Guillain-Barre syndrome (Muller-Fischersyndrome), stiff-man syndrome, cerebellar degeneration, ataxia,opsoclonus, sensoric neuropathy and achalasia, blood diseases such asautoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (MorbusWerlhof), infectious diseases with associated autoimmune reactions suchas AIDS, malaria and Chagas disease.

Compounds of the invention are useful for the treatment of certain typesof cancer by themselves or in combination or co-administration withother therapeutic agents or radiation therapy. Thus, in one embodiment,the compounds of the invention are co-administered with radiationtherapy or a second therapeutic agent with cytostatic or antineoplasticactivity. Suitable cytostatic chemotherapy compounds include, but arenot limited to (i) antimetabolites; (ii) DNA-fragmenting agents, (iii)DNA-crosslinking agents, (iv) intercalating agents (v) protein synthesisinhibitors, (vi) topoisomerase I poisons, such as camptothecin ortopotecan; (vii) topoisomerase II poisons, (viii) microtubule-directedagents, (ix) kinase inhibitors (x) miscellaneous investigational agents(xi) hormones and (xii) hormone antagonists. It is contemplated thatcompounds of the invention may be useful in combination with any knownagents falling into the above 12 classes as well as any future agentsthat are currently in development. In particular, it is contemplatedthat compounds of the invention may be useful in combination withcurrent Standards of Care as well as any that evolve over theforeseeable future. Specific dosages and dosing regimens would be basedon physicians' evolving knowledge and the general skill in the art.

Further provided herein are methods of treatment wherein compounds ofthe invention are administered with one or more immuno-oncology agents.The immuno-oncology agents used herein, also known as cancerimmunotherapies, are effective to enhance, stimulate, and/or up-regulateimmune responses in a subject. In one aspect, the administration of acompound of the invention with an immuno-oncology agent has a synergiceffect in inhibiting tumor growth.

In one aspect, the compound(s) of the invention are sequentiallyadministered prior to administration of the immuno-oncology agent. Inanother aspect, compound(s) of the invention are administeredconcurrently with the immunology-oncology agent. In yet another aspect,compound(s) of the invention are sequentially administered afteradministration of the immuno-oncology agent.

In another aspect, compounds of the invention may be co-formulated withan immuno-oncology agent.

Immuno-oncology agents include, for example, a small molecule drug,antibody, or other biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In one aspect, the antibody is a monoclonalantibody. In another aspect, the monoclonal antibody is humanized orhuman.

In one aspect, the immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses (oftenreferred to as immune checkpoint regulators).

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α 1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In another aspect, the immuno-oncology agent is a cytokine that inhibitsT cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In one aspect, T cell responses can be stimulated by a combination of acompound of the invention and one or more of (i) an antagonist of aprotein that inhibits T cell activation (e.g., immune checkpointinhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4,CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of aprotein that stimulates T cell activation such as B7-1, B7-2, CD28,4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70,CD27, CD40, DR3 and CD28H.

Other agents that can be combined with compounds of the invention forthe treatment of cancer include antagonists of inhibitory receptors onNK cells or agonists of activating receptors on NK cells. For example,compounds of the invention can be combined with antagonists of KIR, suchas lirilumab.

Yet other agents for combination therapies include agents that inhibitor deplete macrophages or monocytes, including but not limited to CSF-1Rantagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In another aspect, compounds of the invention can be used with one ormore of agonistic agents that ligate positive costimulatory receptors,blocking agents that attenuate signaling through inhibitory receptors,antagonists, and one or more agents that increase systemically thefrequency of anti-tumor T cells, agents that overcome distinct immunesuppressive pathways within the tumor microenvironment (e.g., blockinhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), depleteor inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g.,daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolicenzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) andagents that trigger innate immune activation and/or inflammation attumor sites.

In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such asan antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, forexample, YERVOY (ipilimumab) or tremelimumab.

In another aspect, the immuno-oncology agent is a PD-1 antagonist, suchas an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, forexample, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680(AMP-514; WO2012/145493). The immuno-oncology agent may also includepidilizumab (CT-011), though its specificity for PD-1 binding has beenquestioned. Another approach to target the PD-1 receptor is therecombinant protein composed of the extracellular domain of PD-L2(B7-DC) fused to the Fc portion of IgG1, called AMP-224

In another aspect, the immuno-oncology agent is a PD-L1 antagonist, suchas an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include,for example, MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736),BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).

In another aspect, the immuno-oncology agent is a LAG-3 antagonist, suchas an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, forexample, BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321(WO08/132601, WO09/44273).

In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist,such as an agonistic CD137 antibody. Suitable CD137 antibodies include,for example, urelumab and PF-05082566 (WO12/32433).

In another aspect, the immuno-oncology agent is a GITR agonist, such asan agonistic GITR antibody. Suitable GITR antibodies include, forexample, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) andMK-4166 (WO11/028683).

In another aspect, the immuno-oncology agent is an IDO antagonist.Suitable IDO antagonists include, for example, INCB-024360(WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod, orNLG-919 (WO09/73620, WO09/1156652, WO11/56652, WO12/142237).

In another aspect, the immuno-oncology agent is an OX40 agonist, such asan agonistic OX40 antibody. Suitable OX40 antibodies include, forexample, MEDI-6383 or MEDI-6469.

In another aspect, the immuno-oncology agent is an OX40L antagonist,such as an antagonistic OX40 antibody. Suitable OX40L antagonistsinclude, for example, RG-7888 (WO06/029879).

In another aspect, the immuno-oncology agent is a CD40 agonist, such asan agonistic CD40 antibody. In yet another embodiment, theimmuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40antibody. Suitable CD40 antibodies include, for example, lucatumumab ordacetuzumab.

In another aspect, the immuno-oncology agent is a CD27 agonist, such asan agonistic CD27 antibody. Suitable CD27 antibodies include, forexample, varlilumab.

In another aspect, the immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

The combination therapy is intended to embrace administration of thesetherapeutic agents in a sequential manner, that is, wherein eachtherapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single dosage form having afixed ratio of each therapeutic agent or in multiple, single dosageforms for each of the therapeutic agents. Sequential or substantiallysimultaneous administration of each therapeutic agent can be effected byany appropriate route including, but not limited to, oral routes,intravenous routes, intramuscular routes, and direct absorption throughmucous membrane tissues. The therapeutic agents can be administered bythe same route or by different routes. For example, a first therapeuticagent of the combination selected may be administered by intravenousinjection while the other therapeutic agents of the combination may beadministered orally. Alternatively, for example, all therapeutic agentsmay be administered orally or all therapeutic agents may be administeredby intravenous injection. Combination therapy also can embrace theadministration of the therapeutic agents as described above in furthercombination with other biologically active ingredients and non-drugtherapies (e.g., surgery or radiation treatment.) Where the combinationtherapy further comprises a non-drug treatment, the non-drug treatmentmay be conducted at any suitable time so long as a beneficial effectfrom the co-action of the combination of the therapeutic agents andnon-drug treatment is achieved. For example, in appropriate cases, thebeneficial effect is still achieved when the non-drug treatment istemporally removed from the administration of the therapeutic agents,perhaps by days or even weeks.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Pharmaceutical Compositions and Dosing

The invention also provides pharmaceutically acceptable compositionswhich comprise a therapeutically effective amount of one or more of thecompounds of Formula I, formulated together with one or morepharmaceutically acceptable carriers (additives) and/or diluents, andoptionally, one or more additional therapeutic agents described above.As described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets, e.g., those targeted for buccal,sublingual, and systemic absorption, boluses, powders, granules, pastesfor application to the tongue; (2) parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained release formulation; (3) topical application, for example, asa cream, ointment, or a controlled release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the patient being treated and the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, troches and thelike), the active ingredient is mixed with one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds andsurfactants, such as poloxamer and sodium lauryl sulfate; (7) wettingagents, such as, for example, cetyl alcohol, glycerol monostearate, andnon-ionic surfactants; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, zincstearate, sodium stearate, stearic acid, and mixtures thereof; (10)coloring agents; and (11) controlled release agents such as crospovidoneor ethyl cellulose. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard shelled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols andthe like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or non-aqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsuled matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.01 to about 50 mg perkilogram of body weight per day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain aspects of the invention,dosing is one administration per day.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

DEFINITIONS

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

When a substituent is noted as “optionally substituted”, thesubstituents are selected from, for example, substituents such as alkyl,cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl,aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino,disubstituted amines in which the 2 amino substituents are selected fromalkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino,substituted alkanoylamino, substituted arylamino, substitutedaralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono,arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl,arylalkylsulfonyl, sulfonamido, e.g. —SO₂NH₂, substituted sulfonamido,nitro, cyano, carboxy, carbamyl, e.g. —CONH₂, substituted carbamyl e.g.—CONHalkyl, —CONHaryl, —CONHarylalkyl or cases where there are twosubstituents on the nitrogen selected from alkyl, aryl or arylalkyl;alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, e.g.,indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,homopiperazinyl and the like, and substituted heterocyclyl, unlessotherwise defined.

For purposes of clarity and in accordance with standard convention inthe art, the symbol

is used in formulas and tables to show the bond that is the point ofattachment of the moiety or substituent to the core/nucleus of thestructure.

Additionally, for purposes of clarity, where a substituent has a dash(-) that is not between two letters or symbols; this is used to indicatea point of attachment for a substituent. For example, —CONH₂ is attachedthrough the carbon atom.

Additionally, for purposes of clarity, when there is no substituentshown at the end of a solid line, this indicates that there is a methyl(CH₃) group connected to the bond.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Example alkyl groups include,but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyland isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl(e.g., n-pentyl, isopentyl, neopentyl).

The term “alkenyl” denotes a straight- or branch-chained hydrocarbonradical containing one or more double bonds and typically from 2 to 20carbon atoms in length. For example, “C₂-C₈ alkenyl” contains from twoto eight carbon atoms. Alkenyl groups include, but are not limited to,for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl,heptenyl, octenyl and the like.

The term “alkynyl” denotes a straight- or branch-chained hydrocarbonradical containing one or more triple bonds and typically from 2 to 20carbon atoms in length. For example, “C₂-C₈ alkenyl” contains from twoto eight carbon atoms. Representative alkynyl groups include, but arenot limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl and the like.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.Similarly, “alkylthio” or “thioalkoxy” represents an alkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example methyl-S— and ethyl-S—.

The term “aryl”, either alone or as part of a larger moiety such as“aralkyl”, “aralkoxy”, or aryloxyalkyl”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to 15 ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. In certainembodiments of the invention, “aryl” refers to an aromatic ring systemwhich includes, but not limited to phenyl, biphenyl, indanyl,1-naphthyl, 2-naphthyl and terahydronaphthyl. The term “aralkyl” or“arylalkyl” refers to an alkyl residue attached to an aryl ring.Non-limiting examples include benzyl, phenethyl and the like. The fusedaryls may be connected to another group either at a suitable position onthe cycloalkyl ring or the aromatic ring. For example:

Arrowed lines drawn from the ring system indicate that the bond may beattached to any of the suitable ring atoms.

The term “cycloalkyl” refers to cyclized alkyl groups. C₃₋₆ cycloalkylis intended to include C₃, C₄, C₅, and C₆ cycloalkyl groups. Examplecycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkylgroups such as 1-methylcyclopropyl and 2-methylcyclopropyl are includedin the definition of “cycloalkyl”. The term “cycloalkenyl” refers tocyclized alkenyl groups. C₄₋₆ cycloalkenyl is intended to include C₄,C₅, and C₆ cycloalkenyl groups. Example cycloalkenyl groups include, butare not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

The term “cycloalkylalkyl” refers to a cycloalkyl or substitutedcycloalkyl bonded to an alkyl group connected to the carbazole core ofthe compound.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “benzyl,” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle,” “heterocyclyl,” or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “heterocyclylalkyl” refers to a heterocyclyl or substitutedheterocyclyl bonded to an alkyl group connected to the carbazole core ofthe compound.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

The term “electron withdrawing group” (EWG) refers to a substituentwhich polarizes a bond, drawing electron density towards itself and awayfrom other bonded atoms. Examples of EWGs include, but are not limitedto, CF₃, CF₂CF₃, CN, halogen, haloalkyl, NO₂, sulfone, sulfoxide, ester,sulfonamide, carboxamide, alkoxy, alkoxyether, alkenyl, alkynyl, OH,C(O)alkyl, CO₂H, phenyl, heteroaryl, —O-phenyl, and —O— heteroaryl.Preferred examples of EWG include, but are not limited to, CF₃, CF₂CF₃,CN, halogen, SO₂(C₁₋₄ alkyl), CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, andheteroaryl. More preferred examples of EWG include, but are not limitedto, CF₃ and CN.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. and Greene, T. W. Protecting Groups in Organic Synthesis, 4thEdition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology,Vol. 3, Academic Press, New York (1981), the disclosure of which ishereby incorporated by reference. Examples of amine protecting groupsinclude, but are not limited to, the following: (1) acyl types such asformyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromaticcarbamate types such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. The isotopes of hydrogen can be denoted as ¹H (hydrogen),²H (deuterium) and ³H (tritium). They are also commonly denoted as D fordeuterium and T for tritium. In the application, CD₃ denotes a methylgroup wherein all of the hydrogen atoms are deuterium. Isotopes ofcarbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of theinvention can generally be prepared by conventional techniques known tothose skilled in the art or by processes analogous to those describedherein, using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent otherwise employed.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition, Allen, L. V. Jr.,Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,” ATextbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen,P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

f) Rautio, J (Editor). Prodrugs and Targeted Delivery (Methods andPrinciples in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011.

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art. Preparation of prodrugs is well known inthe art and described in, for example, King, F. D., ed., MedicinalChemistry: Principles and Practice, The Royal Society of Chemistry,Cambridge, UK (2^(nd) edition, reproduced, 2006); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, 3^(rd) edition, AcademicPress, San Diego, Calif. (2008).

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms preferably include,but are not limited to, mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and most preferablyrefers to humans.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent, i.e., a compound of the invention, that willelicit the biological or medical response of a tissue, system, animal orhuman that is being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, or amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route. The term also includeswithin its scope amounts effective to enhance normal physiologicalfunction

As used herein, the term “treating” includes any effect, e.g.,lessening, reducing, modulating, ameliorating or eliminating, thatresults in the improvement of the condition, disease, disorder, and thelike, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated by reference in their entirety.

The compounds of this invention may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

Compounds of Formula (I) may be prepared by reference to the methodsillustrated in the following Schemes. As shown therein the end productis a compound having the same structural formula as Formula (I). It willbe understood that any compound of Formula (I) may be produced by theschemes by the suitable selection of reagents with appropriatesubstitution. Solvents, temperatures, pressures, and other reactionconditions may readily be selected by one of ordinary skill in the art.Starting materials are commercially available or readily prepared by oneof ordinary skill in the art. Constituents of compounds are as definedherein or elsewhere in the specification.

General routes to compounds described in the invention are illustratedin Schemes 1-13, where the R¹, R², X, Y, Z and A substituents aredefined previously in the text or a functional group that can beconverted to the desired final substituent. The substituent Hal is ahalide. L is a leaving group such as a halide or OH that can be easilyconverted to a leaving group such as a triflate. As shown in Scheme 1, ageneral procedure for the preparation of compounds of the inventioninvolves starting with the substituted aminopyridine 1. Coupling of 1with the aromatic heterocycle A (2, where M is a suitable couplingpartner, such as boronic acid, boronic ester or stannane) using asuitable catalyst can yield functionalized aminopyridines 3. Forexample, 3 could arise from a Suzuki coupling reaction between5-bromo-2-chloropyridin-3-amine and a heteroaromatic boronic acid usingPd(dppf)Cl₂ as a catalyst. Subsequent coupling to give thefunctionalized aniline 6 can be achieved using a variety of conditionsknown in the literature. For example, aminopyridine 3 can undergocopper-mediated coupling with a suitably substituted arene 4 (where M isa boronic acid, boronic ester or stannane) to give aniline 6.Alternatively, 6 could arise from a Buchwald N-arylation reaction of 3with an aromatic halide 5 (where Hal is a halide). Ring closure togenerate carboline 7 can be achieved using a Pd catalyst in the presenceof a base, such as sodium acetate. In the final step, the carbolinenitrogen can be substituted under Mitsunobu conditions usingtriphenylphosphine and diisopropyl azodicarboxylate (DIAD) with analkylating agent 8 (where X is OH). Alternatively, functionalizedcarboline 10 can be generated from a displacement reaction between thecarboline 7 and an alkylating agent 9, where L is a leaving group suchas a halide, mesylate or triflate, in the presence of a base, such aspotassium carbonate. In cases where 10 is a racemate, chiral separationcan provide enantiomerically pure products. Further derivatization of R¹can provide additional compounds of the invention. For example, when R¹is an ester, addition of a Grignard reagent or alkyl lithium cangenerate tertiary alcohols. The same R¹ ester could instead behydrolyzed using, for example, sodium hydroxide to give a carboxylicacid (R¹═CO₂H) as the final substituent.

An alternative synthesis of the carbolines 7 and 10 starts fromnitropyridine 11 as shown in Schemes 2 to 4. A Suzuki reaction between,for example, 2,5-dibromo-3-nitropyridine and an appropriatelysubstituted arene (12, where M is a suitable coupling partner, such asboronic acid or boronic ester) can give the functionalized pyridine 13.Reductive cyclization mediated by a phosphine reagent, such as1,2-bis(diphenylphosphino)ethane (dppe), can provide carboline 14.Coupling of 14 with the aromatic heterocycle A (2, where M is a suitablecoupling partner, such as boronic acid, boronic ester or stannane) usinga suitable catalyst then generates carboline 7 as shown in Scheme 3.

Alternately, the carboline nitrogen of intermediate 14 can be firstsubstituted under Mitsunobu conditions with an alkylating agent 8 (whereX is OH) or with alkylating agent 9, where L is a leaving group such asa halide, mesylate or triflate, in the presence of a base, such aspotassium carbonate as previously described in Scheme 1 to giveintermediate 15. Then coupling of 15 with the aromatic heterocycle A (2,where M is a suitable coupling partner, such as boronic acid, boronicester or stannane) using a suitable catalyst then generates the finalcarboline 10 as shown in Scheme 4.

An alternate synthesis of carbolines 10 can be achieved as outlined inScheme 5. The leaving group, L, of 15 (prepared as in Scheme 4) can beconverted to a suitable coupling partner, M (preferably a boronic esteror boronic acid) by the action of a palladium catalyst, affording 16.Coupling of 16 with the aromatic heterocycle A (17, where L is asuitable leaving group, such as a halogen or triflate) using a suitablecatalyst can give carbolines 10.

Hydroxymethyl pyrazole derivatives such as 20 can be accessed accordingto Scheme 6. Intermediate 16 (where M is a suitable coupling partnersuch as a boronic acid or boronic ester; prepared as in Scheme 5) can becoupled to an appropriately protected triazole 18 by the action of asuitable catalyst. Triazole 18 is available in one step from acopper-mediated cycloaddition reaction of (azidomethyl)trimethylsilanewith a protected propargyl alcohol. Intermediate 19 can then bedeprotected using a variety of conditions. For example, when PG istert-butyldimethylsilyl, treatment with tetrabutylammonium fluoride cangive the final compound 20. Further derivatization of the hydroxyl group(for example: alkylation, conversion to a leaving group anddisplacement, oxidation to either an aldehyde or carboxylic acid andsubsequent elaboration) can provide additional compounds of theinvention by application of methods which will be readily apparent toone of ordinary skill in the art.

Alternately, intermediate 15 (prepared as in Scheme 4) can be directlycoupled with a suitable aromatic heterocycle, 21, via palladium-mediatedC—H activation to afford compounds 10. This is illustrated in Scheme 7.

Alternately, aromatic heterocycle 21 can be deprotonated with a strongbase such as n-BuLi and transmetallated to zinc, tin, or boron to affordcompounds 2. Compounds 2 can then be coupled in a Negishi, Stille, orSuzuki coupling to intermediate 15 (prepared as in Scheme 4) by theaction of a suitable palladium catalyst to afford compounds 10. This isillustrated in Scheme 8.

An alternate synthesis of carbolines 14 can be achieved as outlined inScheme 9. Aniline 22 can be coupled to pyridine 23, where L and L′ aretwo leaving groups such as halide or triflate, using a BuchwaldN-arylation reaction to give intermediate 24. For example, 24 couldarise from a Buchwald N-arylation reaction between 3,5-dibromopyridineand a suitable aniline. Oxidative ring closure, using an appropriatecatalyst such as Pd(OAc)₂ in an acidic media such as trifluoroaceticacid, can afford carbolines 14. This is illustrated in Scheme 9.

Pyridines 23 (where L and L′ are suitable leaving groups such as halidesor triflates) can also be coupled to aromatic heterocycles 2 (where M isa suitable coupling partner such as a boronic ester, boronic acid, orstannane) or 21 by methods analogous to those illustrated in Schemes 1,3, 4, 7, and 8. Pyridines 25 can be coupled to anilines 22, using aBuchwald N-arylation reaction to give intermediate 26. Oxidative ringclosure, using an appropriate catalyst such as Pd(OAc)₂ in an acidicmedia such as trifluoroacetic acid, can afford carbolines 7. This isillustrated in Scheme 10.

Alkoxy-substituted triazoles 32 can be prepared as illustrated in Scheme11. Aldehyde 27 can be converted to acetal 29 by treatment with alcohol28 (where Alk is a C₁-C₆ alkyl or C₃-C₆ cycloalkyl optionallysubstituted with deuterium) in the presence of acid or a dehydratingagent such as CaCl₂. Acetal 29 can be converted to alkoxy-substitutedalkynes 30 by treatment with a strong base such as lithium diethylamideor sodium amide. Compounds 30 can be converted to triazoles 32 through acopper-catalyzed 3+2 cycoaddition reaction with azide 31. Triazoles 32can be directly coupled to carbolines as illustrated in Scheme 7. Inmost cases, said coupling results in loss of the trimethylsilyl group.In cases where the trimethylsilyl group is not lost, it can be removedby treatment with tetrabutylammonium fluoride.

Alkyl-substituted triazoles 39 can be prepared as illustrated in Scheme12. Acetylene 33 can be alkylated with 34 (where Alk is a C₁-C₆ alkyl orC₃-C₆ cycloalkyl optionally substituted with deuterium and where L is anappropriate leaving group such as iodide, bromide, chloride, orsulfonate) by the action of a strong base such as n-BuLi. Alkyne 35 canbe converted to triazoles 36 through a copper-catalyzed 3+2 cycoadditionreaction with 31. Triazoles 36 can be directly coupled to carbolines asillustrated in Scheme 7. Alternately, the trimethylsilyl group of 36 canbe removed directly by the action of tetrabutyl ammonium fluoride togive N-methyl-triazole 37. Deprotonation of 37 with a strong base suchas n-BuLi, followed by reaction with an appropriate electrophile 38(where L is a leaving group such as a halide or alkoxide and M is anappropriate group to facilitate metal-mediated couplings such astributyltin or a boronic ester; e.g. M-L=Bu₃SnCl or B(OMe)₃) can affordtriazoles 39 which can readily be coupled as illustrated in Schemes 1,3, 4, 8, and 10.

One can vary the substituents of the triazole as shown in Scheme 13. Theleaving group of 34 (where Alk is a C₁-C₆ alkyl or C₃-C₆ cycloalkyloptionally substituted with deuterium and where L is an appropriateleaving group such as iodide, bromide, chloride, or sulfonate) can bedisplaced by treatment with sodium azide to afford 40. Alkynes 41 or 42can be coupled to azides 40 to give triazoles 43 through acopper-catalyzed 3+2 cycoaddition reaction. Triazoles 43 can be directlycoupled to carbolines as illustrated in Scheme 7. Alternately,deprotonation of 43 with a strong base such as n-BuLi, followed byreaction with an appropriate electrophile 38 (where L is a leaving groupsuch as a halide or alkoxide and M is an appropriate group to facilitatemetal-mediated couplings such as tributyltin or a boronic ester; e.g.M-L=Bu₃SnCl or B(OMe)₃) can afford triazoles 44 which can readily becoupled as illustrated in Schemes 1, 3, 4, 8, and 10.

EXAMPLES

The invention is further defined in the following Examples. It should beunderstood that the Examples are given by way of illustration only. Fromthe above discussion and the Examples, one skilled in the art canascertain the essential characteristics of the invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt the invention to various uses and conditions.As a result, the invention is not limited by the illustrative examplesset forth herein below, but rather is defined by the claims appendedhereto.

ABBREVIATIONS MeCN Acetonitrile AcOH acetic acid AlMe₃ trimethylaluminum aq Aqueous Bn Benzyl Boc tert-butoxycarbonyl Boc₂Odi-tert-butyl dicarbonate CBz benzyloxycarbonyl DCC1,3-dicyclohexylcarbodiimide DCM dichloromethane DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIAD diisopropylazodicarboxylate DIEA diisopropylethylamine DMAP 4-dimethylaminopyridineDMA dimethylacetamide DME dimethoxyethane DMF dimethylformamide DMSOdimethyl sulfoxide EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride Et₂AlCl diethyl aluminum chloride Et₃N triethyl amine Et₂Odiethyl ether EtOH Ethanol EtOAc ethyl acetate equiv. equivalent(s) ggram(s) h or hr hour(s) HOBt hydroxybenzotriazole HPLC high pressureliquid chromatography iPrOH isopropyl alcohol KOtBu potassiumtert-butoxide LCMS Liquid Chromatography-Mass Spectroscopy LDA lithiumdiisopropylamide LiHMDS lithium bis(trimethylsilyl)amide Me Methyl MeImethyl iodide MeOH Methanol min minute(s) mL milliliter(s) mmolMillimolar MTBE methyl t-butyl ether NaHMDS sodiumbis(trimethylsilyl)amide n-BuLi n-butyl lithium NH₄OAc ammonium acetateNMP N-methylpyrrolidinone Pd(OAc)₂ palladium acetate Pd(dppf)Cl₂[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) RT or Rtretention time sat Saturated SFC Supercritical fluid chromatography t-Butertiary butyl t-BuLi t-butyl lithium t-BuOH tertiary butyl alcoholt-BuOMe tert-butyl methyl ether TBTUO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateTCTU O-(1H-6-chlorobenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumtetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid Tf₂Otrifluoromethylsulfonic anhydride THF Tetrahydrofuran

The following HPLC conditions may be used where indicated:

Analytical HPLC Method 1: Column: Waters Acquity UPLC BEH C18, 2.1×50mm, 1.7 μm particles; Mobile Phase A: water with 0.05% TFA; Mobile PhaseB: acetonitrile 0.05% TFA; Gradient: 2-98% B over 1 min, then a 0.5-minhold at 98% B; Flow: 0.8 mL/min; Detection: UV at 254 nm.

Analytical HPLC Method 2: Column: Waters Acquity UPLC BEH C18, 2.1×50mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Gradient: 0-100% B over 3 min, then a 0.7-min hold at100% B; Flow: 1.11 mL/min; Detection: UV at 254 nm.

LC/MS Method 1: Column: Phenomenex-Luna 2.0×30 mm, 3 um particles;Mobile Phase A: 10/90 methanol:water, 0.1% TFA; Mobile Phase B: 90/10methanol:water, 0.1% TFA; Temperature 40° C.; Gradient 0% —100% B over 2min; Flow 1 mL/min; Detection: UV at 220 nm.

LC/MS Method 2: Column: Waters Acquity SDS; Mobile Phase A: 100% Water,0.1% TFA; Mobile Phase B: 100% acetonitrile, 0.1% TFA; Temperature 50°C.; Gradient 2%-98% B over 2.2 min; Flow 0.8 mL/min; Detection: UV at220 nm.

LC/MS Method 3: Waters BEH C18, 2.0×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B, 0-100% B over 3 min, then a 0.5-minhold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.

LC/MS Method 4: Waters BEH C18, 2.0×50 mm, 1.7-μm particles; MobilePhase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile PhaseB: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0%-100% B over 3 min, then a 0.5-min hold at 100% B; Flow: 0.5mL/min; Detection: UV at 220 nm.

Preparative HPLC Method 1: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-70% B over 20 min, then a 5-min hold at 100% B;Flow: 20 mL/min.

Preparative HPLC Method 2: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 methanol: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammoniumacetate; Gradient: 35-75% B over 20 min, then a 5-min hold at 100% B;Flow: 20 mL/min.

Preparative HPLC Method 3: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 15-55% B over 20 min, then a 5-min holdat 100% B; Flow: 20 mL/min.

Examples 1 & 22-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 2-Chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine

To a 500 mL round bottom flask containing5-bromo-2-chloropyridin-3-amine (Matrix, 4.0 g, 19.3 mmol) and(3,5-dimethylisoxazol-4-yl)boronic acid (AOBChem, 3.26 g, 23.1 mmol) inTHF (150 mL) was added tripotassium phosphate (2M aq., 28.9 mL, 57.8mmol) to give a yellow suspension. Pd(dppf)Cl₂—CH₂Cl₂ (1.58 g, 1.93mmol) was then added and N₂ was bubbled into the mixture for 4 min. Theresulting reaction mixture was heated at 80° C. for 1 h, concentratedand then diluted with 10% LiCl solution and extracted with CH₂Cl₂. Theorganic layer was concentrated and filtered through Celite®. The motherliquor was purified using ISCO silica gel chromatography (220 g column,gradient from 0% to 50% EtOAc/CH₂Cl₂). Trituration with cold Et₂O gavethe title compound (3.14 g, 73%) as a pale orange solid. ¹H NMR (400MHz, CDCl₃) δ 7.71 (d, J=2.1 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 4.20 (br.s., 2H), 2.42 (s, 3H), 2.27 (s, 3H); LCMS (M+H)=224.1. HPLC RT=1.39 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2: Methyl3-((2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)benzoate

To a 250 mL round bottom flask containing2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine (2.0 g, 8.9 mmol),(3-(methoxycarbonyl)phenyl)boronic acid (Aldrich, 3.22 g, 17.9 mmol),Cu(OAc)₂ (2.43 g, 13.4 mmol) and powdered 4 Å molecular sieves (7.0 g)was added CHCl₃ (50 mL) and pyridine (1.45 mL, 17.9 mL). The atmospherewas exchanged with O₂, and the reaction was stirred under an O₂ balloonfor 6 h. Additional (3-(methoxycarbonyl)phenyl)boronic acid (3.22 g,17.9 mmol), pyridine (1.45 mL, 17.9 mmol) and 4 Å molecular sieves (1.7g) were added. The reaction mixture was stirred at room temperatureovernight. Additional (3-(methoxycarbonyl)phenyl)boronic acid (3.22 g,17.9 mmol), pyridine (1.45 mL, 17.9 mmol) and Cu(OAc)₂ (400 mg) wereadded to the reaction. After stirring at room temperature for 7 h, thereaction mixture was filtered through Celite® rinsing with CHCl₃. Thefiltrate was diluted with water and ammonium hydroxide (18.6 mL, 143mmol) was added. The aqueous layer was extracted with CHCl₃ and thecombined organic layers were washed with 10% LiCl. The organic layer wasconcentrated and purified by silica gel chromatography (220 g column,gradient from 0% to 50% EtOAc/CH₂Cl₂). The fractions were concentratedin vacuo until a white precipitate formed which collected via filtrationand rinsed with EtOAc to give the title compound (1.33 g, 57%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (t, J=1.8 Hz, 1H), 7.85 (d,J=2.1 Hz, 1H), 7.82 (dt, J=7.7, 1.3 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H),7.40 (d, J=2.1 Hz, 1H), 7.36 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 6.32 (s,1H), 3.94 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H); LCMS (M+H)=358.2; HPLCRT=2.70 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 3: Methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a 40 mL vial containing methyl3-((2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)benzoate(515 mg, 1.44 mmol) and sodium acetate trihydrate (480 mg, 3.52 mmol) inDMA (5.0 mL) was added bis(triphenylphosphine)palladium(II) chloride (81mg, 0.12 mmol). N₂ was bubbled through the reaction mixture for 1 min.The vial was capped and heated at 180° C. for 15-30 min. The reactionmixture was then concentrated and purified directly using ISCO silicagel chromatography (40 g column, gradient from 0% to 100% EtOAc/CH₂Cl₂).The resulting orange oil was dissolved in EtOAc (7 mL) and stirred atroom temperature overnight. The resulting yellow precipitate wascollected via filtration and washed with EtOAc. The mother liquor wasconcentrated and repurified using ISCO silica gel chromatography (40 gcolumn, gradient from 0% to 50% EtOAc/CH₂Cl₂). After trituration withcold EtOAc, the solids were combined to give the title compound (301 mg,65%). HPLC RT=2.01 min (Column: Chromolith ODS S5 4.6×50 mm; MobilePhase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 4: Methyl3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a 5 mL vial containing methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (87mg, 0.27 mmol) and phenyl(tetrahydro-2H-pyran-4-yl)methanol (104 mg,0.54 mmol) [Orjales, A. et al. J. Med. Chem. 2003, 46, 5512-5532] in THF(2.0 mL) was added Ph₃P (141 mg, 0.54 mmol) and DIAD (0.11 mL, 0.54mmol). The resulting suspension was stirred at room temperatureovernight and then concentrated. The residue was purified using ISCOsilica gel chromatography (40 g column, gradient from 0% to 50%EtOAc/CH₂Cl₂) to give the title compound (139 mg) as an impure mixturewhich was carried on to the subsequent step without furtherpurification. LCMS (M+H)=496.2; HPLC RT=3.06 min (Column: Chromolith ODSS5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Step 5:2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

A 250 mL round bottom flask containing methyl3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(1.58 g, 3.19 mmol) in CH₂Cl₂ (50 mL) was cooled in an ice/MeOH bath.MeMgBr, (3M in Et₂O, 17.0 mL, 51.0 mmol) was added slowly over 2 min.The resulting suspension was stirred for 2.5 h and then quenchedcarefully with sat. NH₄Cl. Ice was added to the reaction mixturefollowed by 10% LiCl solution. The aqueous layer was extracted withCH₂Cl₂ (2×). The organic layer was dried over MgSO₄, filtered andconcentrated to give racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated using chiral prep SFC (Column: Chiral OD-H 25×3 cm,5 μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 85 mL/min). The faster elutingpeak was concentrated to a small volume. Water was added to form a whiteprecipitate which was collected via filtration, rinsing with water, togive a white solid which was assigned as Enantiomer A (0.59 g, 36%). Theslower eluting peak was treated in an identical manner and assigned asEnantiomer B (0.51 g, 31%). Enantiomer A: ¹H NMR (500 MHz, CDCl₃) δ 8.40(d, J=1.8 Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.53 (d, J=1.8Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.42 (dd, J=8.2, 1.4 Hz, 1H), 7.37-7.31(m, 2H), 7.30-7.28 (m, 1H), 5.56 (d, J=10.5 Hz, 1H), 4.06 (d, J=8.9 Hz,1H), 3.89-3.83 (m, 1H), 3.55 (td, J=11.9, 2.1 Hz, 1H), 3.35 (td, J=11.9,2.1 Hz, 1H), 3.10 (q, J=10.8 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H), 2.03(d, J=14.2 Hz, 1H), 1.89 (s, 1H), 1.74 (s, 6H), 1.68-1.59 (m, 1H),1.46-1.36 (m, 1H), 1.12 (d, J=12.2 Hz, 1H); LCMS (M+H)=496.4; HPLCRT=2.46 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min); SFC RT=5.36 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ¹H NMR (500MHz, CDCl₃) δ 8.40 (d, J=1.8 Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.94 (s,1H), 7.53 (d, J=1.8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.42 (dd, J=8.2,1.4 Hz, 1H), 7.36-7.31 (m, 2H), 7.30-7.28 (m, 1H), 5.56 (d, J=10.7 Hz,1H), 4.06 (dd, J=11.7, 2.5 Hz, 1H), 3.86 (dd, J=11.5, 2.8 Hz, 1H), 3.55(td, J=11.9, 2.1 Hz, 1H), 3.35 (td, J=11.9, 2.0 Hz, 1H), 3.15-3.05 (m,1H), 2.39 (s, 3H), 2.23 (s, 3H), 2.03 (d, J=13.6 Hz, 1H), 1.90 (s, 1H),1.74 (s, 6H), 1.68-1.58 (m, 1H), 1.46-1.36 (m, 1H), 1.12 (d, J=12.4 Hz,1H); LCMS (M+H)=496.4; HPLC RT=2.46 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min); SFC RT=14.95 min (Column: Chiralcel OD-H250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min).

Examples 3-24

The compounds in Table 1 were prepared according to the proceduresdescribed for Example 1:

TABLE 1 HPLC RT LCMS Optical Rotation HPLC Example X Y (min) (M + H)[α]_(D) ²⁰ Method  3

2.92 488.1 N/A A  4

1.79 392.2 N/A B  5 (racemate)

2.42 456.4 N/A A  6

1.98 527.2 N/A B  7

1.51 423.2 N/A B  8

2.66 420.4 N/A A  9 Enantiomer A

3.25 508.4 −43.39 (c = 0.10, CHCl₃) C 10 Enantiomer B

9.44 508.4 N/A C 11 Enantiomer A

9.40 452.4 N/A D 12 Enantiomer B

14.11 452.4 +32.61 (c = 0.07, CHCl₃) D 13 Enantiomer A

6.50 466.5 −73.83 (c = 0.06, CHCl₃) D 14 Enantiomer B

10.66 466.5 +75.20 (c = 0.09, CHCl₃) D 15 Enantiomer A

13.60 484.4 −70.71 (c = 0.54, MeOH) E 16 Enantiomer B

16.61 484. 4 +52.84 (c = 0.60, MeOH) E 17 Enantiomer A

14.82 542.5 −118.89  (c = 0.11, MeOH) E 18 Enantiomer B

9.14 542.5 N/A E 19 Enantiomer A

5.06 515.3 −52.83 (c = 0.41, MeOH) C 20 Enantiomer B

6.82 515.3 +50.15 (c = 0.43, MeOH) C 21 Enantiomer A

9.20 497.5 −133.04  (c = 0.08, MeOH) C 22 Enantiomer B

11.94 497.5 +133.47  (c = 0.08, MeOH) C 23 Enantiomer A

4.38 509.4 −79.87 (c = 0.30, MeOH) C 24 Enantiomer B

5.31 509.4 +79.60 (c = 0.33, MeOH) C

HPLC Conditions for Table 1:

Method A:

-   -   Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90        MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with        0.1% TFA;    -   Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4        mL/min; Detection: UV at 220 nm.

Method B:

-   -   Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm        particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM        ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with        10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B        over 3 min, then a 0.75-min hold at 100% B; Flow: 1.11 mL/min;        Detection: UV at 220 nm.

Method C:

-   -   Column: Chiralcel OD-H 250×4.6 mm, 5 μm particles; Mobile Phase:        80/20 CO₂/MeOH; Flow: 2 mL/min; Detection UV at 220 nm.

Method D:

-   -   Column: Chiralpak IB, 250×4.6 mm, 5 μm particles; Mobile Phase:        80/20 CO₂/MeOH; Flow: 2 mL/min; Detection UV at 220 nm.

Method E:

-   -   Column: Phenomenex Lux Cellulose 2, 250×4.6 mm, 5 μm particles;        Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min; Detection UV at        220 nm.

Examples 25 & 262-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (4-Fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol

To a 40 mL vial containing magnesium (0.39 g, 16.1 mmol) in THF (15 mL)was slowly added 4-bromotetrahydro-2H-pyran (PharmaBlock, 1.8 mL, 16.1mmol) cooling in a water bath as needed. The resulting reaction mixturewas stirred at room temperature for 1.5 h and then cooled in a waterbath. 4-Fluorobenzaldehyde (Aldrich, 1.2 mL, 10.7 mmol) was addedslowly. The resulting orange reaction mixture was removed from the waterbath and quenched with sat. NH₄Cl after 10 min. 10% LiCl solution wasadded and the mixture was extracted with Et₂O (2×). The organic layerwas dried over MgSO₄, filtered and concentrated. The residue waspurified using ISCO silica gel chromatography (80 g column, gradientfrom 0% to 50% EtOAc/hexanes) to give the title compound (1.12 g, 33%)as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.27 (m, 2H),7.08-7.02 (m, 2H), 4.37 (dd, J=0.7, 2.4 Hz, 1H), 4.06-3.99 (m, 1H),3.94-3.87 (m, 1H), 3.37 (td, J=11.9, 2.2 Hz, 1H), 3.29 (td, J=11.8, 2.3Hz, 1H), 1.94-1.87 (m, 2H), 1.81 (tdt, J=11.6, 7.7, 3.8 Hz, 1H), 1.45(qd, J=12.3, 4.7 Hz, 1H), 1.36-1.27 (m, 1H), 1.16 (ddq, J=13.2, 3.9, 2.0Hz, 1H); LCMS (M+H-H₂O)=193.1; HPLC RT=1.65 min (Column: Chromolith ODSS5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Step 2:2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 ofExample 1, methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (100mg, 0.31 mmol) and (4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol(131 mg, 0.62 mmol) were converted to racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (18 mg, 11%)and Enantiomer B (22 mg, 12%). Enantiomer A: ¹H NMR (500 MHz, CDCl₃) δ8.41 (d, J=1.8 Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.91 (s, 1H), 7.50 (d,J=1.5 Hz, 1H), 7.46-7.37 (m, 3H), 7.06-6.99 (m, 2H), 5.53 (d, J=10.5 Hz,1H), 4.07 (dd, J=11.7, 2.5 Hz, 1H), 3.87 (dd, J=11.8, 3.0 Hz, 1H), 3.54(td, J=11.9, 2.1 Hz, 1H), 3.34 (td, J=11.9, 2.1 Hz, 1H), 3.11-3.01 (m,1H), 2.41 (s, 3H), 2.25 (s, 3H), 1.98 (d, J=13.4 Hz, 1H), 1.89 (s, 1H),1.73 (s, 6H), 1.66-1.59 (m, 1H), 1.46-1.36 (m, 1H), 1.13 (d, J=13.3 Hz,1H); LCMS (M+H)=514.4; HPLC RT=2.55 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min); SFC RT=6.56 min (Column: Chiralcel OD-H250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min).Enantiomer B: ¹H NMR (500 MHz, CDCl₃) δ 8.41 (d, J=1.8 Hz, 1H), 8.33 (d,J=8.2 Hz, 1H), 7.91 (s, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.46-7.37 (m, 3H),7.06-6.99 (m, 2H), 5.53 (d, J=10.5 Hz, 1H), 4.07 (dd, J=11.7, 2.5 Hz,1H), 3.87 (dd, J=11.8, 3.0 Hz, 1H), 3.54 (td, J=11.9, 2.1 Hz, 1H), 3.34(td, J=11.9, 2.1 Hz, 1H), 3.11-3.01 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H),1.98 (d, J=13.4 Hz, 1H), 1.89 (s, 1H), 1.73 (s, 6H), 1.66-1.59 (m, 1H),1.46-1.36 (m, 1H), 1.13 (d, J=13.3 Hz, 1H); LCMS (M+H)=514.4; HPLCRT=2.55 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min); SFC RT=8.58 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=+89.91,(c=0.14, CHCl₃).

Examples 27 & 282-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: (4,4-Difluorocyclohexyl)(phenyl)methanone

To a 50 mL round bottom flask containing4,4-difluoro-N-methoxy-N-methylcyclohexanecarboxamide (500 mg, 2.41mmol) [Lehmann-Lintz, T. et al. PCT Int. Appl., 2011, WO2011104334] inTHF (10 mL) at −78° C. was slowly added phenyllithium (1.8M in dibutylether, 4.69 mL, 8.45 mmol). After 1 h, the reaction mixture was pouredinto ice and 1M HCl (10.8 mL, 10.8 mmol) with stirring. The mixture wasdiluted with sat. NaCl and extracted with Et₂O. The organic layer wasdried over MgSO₄, filtered and concentrated to give the title compound(532 mg, 98%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.89 (m,2H), 7.64-7.55 (m, 1H), 7.54-7.44 (m, 2H), 3.46-3.27 (m, 1H), 2.36-2.11(m, 2H), 2.09-1.73 (m, 6H); HPLC RT=2.39 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Step 2: (4,4-Difluorocyclohexyl)(phenyl)methanol

To a 100 mL round bottom flask containing(4,4-difluorocyclohexyl)(phenyl) methanone (532 mg, 2.37 mmol) in MeOH(15 mL) in an ice water bath was added NaBH₄ (135 mg, 3.56 mmol) insmall portions over 20 seconds. After stirring in the ice water bath for30 min, the reaction mixture was diluted with water and concentrated.The residue was acidified to pH 6 with 1N citric acid and extracted withCH₂Cl₂ (2×). The organic layer was dried over MgSO₄, filtered andconcentrated to give the crude title compound (562 mg) which was used inthe subsequent step without further purification. HPLC RT=2.35 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 3:2-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 ofExample 1, methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (80mg, 0.25 mmol) and (4,4-difluorocyclohexyl)(phenyl)methanol (141 mg,0.62 mmol) were converted to racemic2-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (23 mg, 30%)and Enantiomer B (23 mg, 30%). Enantiomer A: ¹H NMR (500 MHz, CDCl₃) δ8.40 (d, J=1.7 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.93 (s, 1H), 7.51 (d,J=1.7 Hz, 1H), 7.47-7.39 (m, 3H), 7.37-7.32 (m, 2H), 7.31-7.28 (m, 1H),5.56 (d, J=10.5 Hz, 1H), 2.94 (d, J=8.1 Hz, 1H), 2.39 (s, 3H), 2.28-2.15(m, 5H), 2.05-1.83 (m, 3H), 1.77-1.72 (m, 6H), 1.71-1.58 (m, 2H),1.44-1.31 (m, 2H); LCMS (M+H)=530.4; HPLC RT=2.81 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFC RT=3.54 min(Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/MeOH;Flow: 2 mL/min); [α]_(D) ²⁰=−101.98, (c=0.07, CHCl₃). Enantiomer B: ¹HNMR (500 MHz, CDCl₃) δ 8.40 (d, J=1.7 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H),7.93 (s, 1H), 7.51 (d, J=1.7 Hz, 1H), 7.47-7.39 (m, 3H), 7.37-7.32 (m,2H), 7.31-7.28 (m, 1H), 5.56 (d, J=10.5 Hz, 1H), 2.94 (d, J=8.1 Hz, 1H),2.39 (s, 3H), 2.28-2.15 (m, 5H), 2.05-1.83 (m, 3H), 1.77-1.72 (m, 6H),1.71-1.58 (m, 2H), 1.44-1.31 (m, 2H); LCMS (M+H)=530.4; HPLC RT=2.81 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFCRT=7.58 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:70/30 CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=+104.36, (c=0.10, CHCl₃).

Examples 29 & 302-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[phenyl(1,3-thiazol-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Phenyl(thiazol-4-yl)methanol

A solution of thiazole-4-carbaldehyde (0.32 g, 2.83 mmol) in THF (18.9mL) was cooled to 0° C. Phenylmagnesium bromide (3M in Et₂O, 2.83 mL,8.49 mmol) was added. After 1.5 h, the reaction was quenched with sat.NH₄Cl, then diluted with water. The reaction was extracted with EtOAc,and the organic layer was washed with sat. NaCl, dried with Na₂SO₄ andconcentrated. The residue was purified using ISCO silica gelchromatography (40 g column, gradient from 0% to 100% EtOAc/hexanes) togive the title compound (0.45 g, 82%). ¹H NMR (400 MHz, CDCl₃) δ 8.80(d, J=2.1 Hz, 1H), 7.49-7.44 (m, 2H), 7.42-7.36 (m, 2H), 7.35-7.29 (m,1H), 7.13 (dd, J=2.0, 0.9 Hz, 1H), 6.01 (d, J=4.2 Hz, 1H), 2.94 (d,J=4.3 Hz, 1H); LCMS (M+H—H₂O)=174.1.

Step 2:2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[phenyl(1,3-thiazol-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 ofExample 1, methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (80mg, 0.25 mmol) and phenyl(thiazol-4-yl)methanol (95 mg, 0.50 mmol) wereconverted to racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[phenyl(1,3-thiazol-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (10 mg, 8%)and Enantiomer B (10 mg, 8%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ9.05 (d, J=2.0 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H),7.72 (s, 1H), 7.57 (s, 1H), 7.53-7.44 (m, 3H), 7.39-7.33 (m, 3H),7.27-7.18 (m, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.58 (s, 6H); LCMS(M+H)=495.4; HPLC RT=7.24 min (Column: Sunfire C18 3.5 μm, 3.0×150 mm;Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B:95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min;Flow: 0.5 mL/min; Detection: UV at 220 nm); SFC RT=8.45 min (Column:Chiralpak AD-H, 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2mL/min); [α]_(D) ²⁰=+42.45, (c=0.06, CHCl₃). Enantiomer B: ¹H NMR (400MHz, CD₃OD) δ 9.05 (d, J=2.0 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H), 8.30 (d,J=8.4 Hz, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.53-7.44 (m, 3H), 7.39-7.33(m, 3H), 7.27-7.18 (m, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.58 (s, 6H);LCMS (M+H)=495.4; HPLC RT=7.24 min (Column: Sunfire C18 3.5 μm, 3.0×150mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile PhaseB: 95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15min; Flow: 0.5 mL/min; Detection: UV at 220 nm); SFC RT=11.91 min(Column: Chiralpak AD-H, 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH;Flow: 2 mL/min); [α]_(D) ²⁰=−35.86, (c=0.06, CHCl₃).

Example 312-[5-(Dicyclobutylmethyl)-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Dicyclobutylmethanol

To a suspension of magnesium (0.58 g, 23.8 mmol) in THF (32 mL) wasadded 4 drops of 1,2-dibromoethane. The suspension was heated to 50° C.,then bromocyclobutane (3.21 g, 23.8 mmol) was added dropwise. Thereaction was cooled in an ice bath, then cyclobutanecarbaldehyde (1.0 g,11.9 mmol) in THF (7.9 mL) was added. After 1 h, the reaction wasquenched with sat. NH₄Cl, then extracted with EtOAc. The organic layerwas washed with sat. NaCl, dried with Na₂SO₄ and concentrated. Theresidue was purified using ISCO silica gel chromatography (40 g column,gradient form 0% to 50% EtOAc/hexanes) to give the title compound (1.04g, 62%). ¹H NMR (400 MHz, CDCl₃) δ 3.40 (td, J=6.9, 4.8 Hz, 1H),2.38-2.23 (m, 2H), 1.98-1.68 (m, 12H), 1.30-1.27 (m, 1H).

Step 2: Methyl5-(dicyclobutylmethyl)-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a suspension of methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (100mg, 0.31 mmol) and dicyclobutylmethanol (87 mg, 0.62 mmol) in toluene(3.1 mL) was added 2-(trimethylphosphoranylidene)acetonitrile (0.5M inTHF, 1.2 mL, 0.62 mmol). The reaction mixture was heated to 110° C.overnight. Additional dicyclobutylmethanol (87 mg, 0.62 mmol) and2-(trimethylphosphoranylidene)acetonitrile (0.5M in THF, 1.2 mL, 0.62mmol) were added and stirring was continued overnight. The reactionmixture was concentrated, and the residue was purified using ISCO silicagel chromatography (24 g column, gradient from 0% to 50% EtOAc/hexanes)to give the title compound (57 mg, 41%). LCMS (M+H)=444.5.

Step 3:2-[5-(Dicyclobutylmethyl)-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described in Step 5 of Example1, methyl5-(dicyclobutylmethyl)-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(80 mg, 0.25 mmol) was converted to the title compound (19 mg, 30%) asan inseparable mixture of atropisomers after purification by prep HPLC(Column: Phen Luna C18, 30×100 mm, 5 μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.1% TFA; Gradient: 10-100% B over 14 min, thena 2-min hold at 100% B; Flow: 40 mL/min). LCMS (M+H)=444.5; HPLC RT=6.96min (Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min; Flow:0.5 mL/min; Detection: UV at 220 nm).

Example 32 & 332-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(1-fluorocyclobutyl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (1-Fluorocyclobutyl)(phenyl)methanone

A suspension of Accufluor™ NFTh (Aldrich, 50% on alumina, 6.03 g, 9.36mmol) and cyclobutyl(phenyl)methanone (0.75 g, 4.68 mmol) [Bauser, M. etal. PCT Int. Appl., 2005, WO2005039569] in MeOH (46.8 ml) was dividedbetween two 40 mL pressure vials and stirred overnight at 70° C.Additional Accufluor™ NFTh (2.0 g) was added and heating was continuedovernight. The reaction was cooled, then decanted and concentrated.CH₂Cl₂ was added, and the insoluble material was filtered off. Theorganic layer was washed sequentially with water and sat. NaCl, thendried with Na₂SO₄ and concentrated to give the crude title compound (600mg, 72%), which was used in the subsequent step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 7.90-8.05 (2H, m), 7.52-7.63(1H, m), 7.41-7.50 (2H, m), 2.71-2.91 (2H, m), 2.42-2.64 (2H, m), 2.00(1H, dd, J=11.1, 3.7 Hz), 1.74 (1H, dtd, J=11.2, 8.9, 8.9, 2.3 Hz)

Step 2: (1-Fluorocyclobutyl)(phenyl)methanol

A solution of (1-fluorocyclobutyl)(phenyl)methanone (0.780 g, 4.38 mmol)in MeOH (14.59 ml) was cooled to 0° C. and NaBH₄ (0.248 g, 6.57 mmol)was added portionwise. After 1 hour a small amount of water was added,then the reaction was concentrated. The residue was suspended in CH₂Cl₂,then sat. NH4Cl solution was added carefully. The layers were separated,and then the aqueous layer was reextracted with CH₂Cl₂. The organiclayer was washed with brine, dried with sodium sulfate and concentrated.The residue was purified via ISCO (40 g column; Hex/EtOAc; 0 to 30%gradient) to give (1-fluorocyclobutyl)(phenyl)methanol (0.651 g, 3.61mmol, 83% yield). 1H NMR (400 MHz, CDCl₃) δ 7.48-7.43 (m, 2H), 7.41-7.31(m, 3H), 4.77 (dd, J=18.5, 4.7 Hz, 1H), 2.48-2.13 (m, 5H), 1.83-1.70 (m,1H), 1.25-1.13 (m, 1H). 19F NMR (376 MHz, CDCl₃) δ −142.70 (s, 1F)

Step 3:2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(1-fluorocyclobutyl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 ofExample 1, methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (75mg, 0.23 mmol) and (1-fluorocyclobutyl)(phenyl)methanol (84 mg, 0.47mmol) were converted to racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(1-fluorocyclobutyl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (29 mg, 18%)and Enantiomer B (30 mg, 19%). Enantiomer A: ¹H NMR (400 MHz, CDCl₃) δ8.39-8.35 (m, 2H), 7.89 (br s, 1H), 7.47 (dd, J=8.2, 1.3 Hz, 1H),7.31-7.28 (m, 6H), 6.27-6.10 (m, 1H), 2.92-2.65 (m, 2H), 2.40-2.26 (m,2H), 2.25 (s, 3H), 2.06 (s, 3H), 1.95-1.83 (m, 2H), 1.74 (s, 6H); LCMS(M+H)=484.5; HPLC RT=8.20 min (Column: Sunfire C18 3.5 μm, 3.0×150 mm;Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B:95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min;Flow: 0.5 mL/min; Detection: UV at 220 nm). SFC RT=6.57 (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2mL/min); [α]_(D) ²⁰=−10.66 (c=0.08, CHCl₃). Enantiomer B: ¹H NMR (400MHz, CDCl₃) δ 8.39-8.35 (m, 2H), 7.89 (br s, 1H), 7.47 (dd, J=8.2, 1.3Hz, 1H), 7.31-7.28 (m, 6H), 6.27-6.10 (m, 1H), 2.92-2.65 (m, 2H),2.40-2.26 (m, 2H), 2.25 (s, 3H), 2.06 (s, 3H), 1.95-1.83 (m, 2H), 1.74(s, 6H); LCMS (M+H)=484.5; HPLC RT=8.20 min (Column: Sunfire C18 3.5 μm,3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100%B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220 nm). SFC RT=13.73(Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH;Flow: 2 mL/min); [α]_(D) ²⁰=+15.73 (c=0.08, CHCl₃).

Example 34 and 352-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[4,4,4-trifluoro-1-(1,3-oxazol-4-yl)butyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: N-Methoxy-N-methyloxazole-4-carboxamide

A suspension of oxazole-4-carboxylic acid (0.50 g, 4.42 mmol) and HOBT(0.74 g, 4.86 mmol) was stirred for 10 min and thenN,O-dimethylhydroxylamine, HCl (0.47 g, 4.86 mmol) and DIEA (0.85 mL,4.86 mmol) were added. After 10 min, EDC (0.93 g, 4.86 mmol) was added.The resulting reaction mixture was stirred overnight and then dilutedwith 1M HCl. The layers were separated, and the aqueous layer wasextracted with CH₂Cl₂. The organic layer was washed sequentially withsat. NaHCO₃ and sat. NaCl, dried over Na₂SO₄ and concentrated to givethe title compound (0.22 g, 33%). ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s,1H), 7.93 (s, 1H), 3.78 (s, 3H), 3.41 (s, 3H).

Step 2: 4,4,4-Trifluoro-1-(oxazol-4-yl)butan-1-one

To a suspension of magnesium (0.070 g, 2.88 mmol) in THF (15 mL) wasadded 2 drops of 1,2-dibromoethane followed by a solution of3-bromo-1,1,1-trifluoropropane (0.51 g, 2.88 mmol) in THF (5.0 mL). Theresulting reaction mixture was cooled to 0° C., and then a suspension ofN-methoxy-N-methyloxazole-4-carboxamide (0.22 g, 1.44 mmol) in THF (5.0mL) was added. After 1.5 h, the reaction was quenched with sat. NH₄Cl,and then extracted with EtOAc (2×). The combined organic layer waswashed with sat. NaCl, dried with Na₂SO₄ and concentrated to the titlecompound (0.25 g, 89% yield), which was used without furtherpurification in the subsequent step. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d,J=1.0 Hz, 1H), 7.94 (d, J=0.7 Hz, 1H), 3.31-3.19 (m, 2H), 2.57 (dt,J=10.8, 7.7 Hz, 2H).

Step 3: 4,4,4-Trifluoro-1-(oxazol-4-yl)butan-1-ol

A solution of 4,4,4-trifluoro-1-(oxazol-4-yl)butan-1-one (0.25 g, 1.28mmol) in MeOH (4.3 mL) was cooled to 0° C. and NaBH₄ (0.073 g, 1.92mmol) was added. After 1.5 h, a small amount of water was added and thereaction mixture was concentrated. The residue was diluted with CH₂Cl₂,then carefully quenched with sat. NH₄Cl. The layers were separated, andthe aqueous layer extracted with CH₂Cl₂. The combined organic layer wasdried with Na₂SO₄ and concentrated. The residue was purified using ISCOsilica gel chromatography (24 g column, gradient from 0% to 100%EtOAc/hexanes) to give the title compound (0.16 g, 63%). ¹H NMR (400MHz, CDCl₃) δ 7.88 (s, 1H), 7.62 (t, J=0.9 Hz, 1H), 4.85-4.76 (m, 1H),2.40 (d, J=5.4 Hz, 1H), 2.38-2.19 (m, 2H), 2.16-2.06 (m, 2H).

Step 4:2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[4,4,4-trifluoro-1-(1,3-oxazol-4-yl)butyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 ofExample 1, methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (100mg, 0.31 mmol) and 4,4,4-trifluoro-1-(oxazol-4-yl)butan-1-ol, (91 mg,0.47 mmol) were converted to racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[4,4,4-trifluoro-1-(1,3-oxazol-4-yl)butyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (26 mg, 17%)and Enantiomer B (27 mg, 17%). Enantiomer A: ¹H NMR (500 MHz, CD₃OD) δ8.41 (d, J=1.7 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.17 (s, 1H), 8.12 (s,1H), 8.04 (d, J=1.6 Hz, 1H), 7.88 (s, 1H), 7.51 (dd, J=8.4, 1.3 Hz, 1H),6.16 (dd, J=10.2, 5.4 Hz, 1H), 2.98-2.73 (m, 2H), 2.47 (s, 3H), 2.37(dt, J=14.9, 5.6 Hz, 1H), 2.30 (s, 3H), 1.91-1.76 (m, 1H), 1.64 (s, 6H);LCMS (M+H)=499.5; HPLC RT=7.19 min (Column: Sunfire C18 3.5 μm, 3.0×150mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile PhaseB: 95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15min; Flow: 0.5 mL/min; Detection: UV at 220 nm). SFC RT=4.21 min(Column: Phenomenex LUX Cellulose 2 250×4.6 mm, 5 μm; Mobile Phase:80/20 CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=+16.38 (c=0.17, CHCl₃).Enantiomer B: ¹H NMR (500 MHz, CD₃OD) δ 8.41 (d, J=1.7 Hz, 1H), 8.30 (d,J=8.4 Hz, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 8.04 (d, J=1.6 Hz, 1H), 7.88(s, 1H), 7.51 (dd, J=8.4, 1.3 Hz, 1H), 6.16 (dd, J=10.2, 5.4 Hz, 1H),2.98-2.73 (m, 2H), 2.47 (s, 3H), 2.37 (dt, J=14.9, 5.6 Hz, 1H), 2.30 (s,3H), 1.91-1.76 (m, 1H), 1.64 (s, 6H); LCMS (M+H)=499.5; HPLC RT=7.19 min(Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min; Flow:0.5 mL/min; Detection: UV at 220 nm). SFC RT=5.10 min (Column:Phenomenex LUX Cellulose 2 250×4.6 mm, 5 μm; Mobile Phase: 80/20CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=−9.16 (c=0.08, CHCl₃).

Example 36 & Example 372-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[4,4,4-trifluoro-1-(1,2-oxazol-4-yl)butyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 4,4,4-Trifluoro-1-(isoxazol-4-yl)butan-1-ol

A mixture of 3-bromo-1,1,1-trifluoropropane (1.37 g, 7.73 mmol),magnesium (0.19 g, 7.73 mmol) and dibromoethane (2-3 drops) in THF (13mL) was heated to 50° C. for 30 min. The reaction mixture was thencooled in ice bath and isoxazole-4-carbaldehyde (0.50 g, 5.15 mmol) inTHF (5.0 mL) was added slowly. The mixture was stirred at roomtemperature for 3 h and then quenched with sat. NH₄Cl (3 mL) and dilutedwith water. The aqueous layer was extracted with EtOAc (3×). The organiclayer was separated, concentrated and the residue was purified by ISCOsilica gel chromatography (40 g column, gradient from 0% to 40%EtOAc/hexanes) to afford the title compound (710 mg, 71%) as a colorlesssolid. ¹H NMR (400 MHz, CD₃OD) δ 8.63 (d, J=0.7 Hz, 1H), 8.45 (s, 1H),4.77 (dd, J=8.1, 4.9 Hz, 1H), 2.48-2.17 (m, 2H), 2.08-1.86 (m, 2H).

Step 2:2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[4,4,4-trifluoro-1-(1,2-oxazol-4-yl)butyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 ofExample 1, methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (75mg, 0.23 mmol) and 4,4,4-trifluoro-1-(isoxazol-4-yl)butan-1-ol, (68 mg,0.35 mmol) were converted to racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[4,4,4-trifluoro-1-(1,2-oxazol-4-yl)butyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (6 mg, 5%)and Enantiomer B (5 mg, 4%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ ¹HNMR (400 MHz, CD₃OD) δ 8.89 (d, J=1.1 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H),8.34 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 7.84 (d, J=14.5 Hz, 2H), 7.53 (dd,J=8.3, 1.2 Hz, 1H), 6.21 (dd, J=11.1, 4.5 Hz, 1H), 3.01-2.87 (m, 1H),2.83-2.71 (m, 1H), 2.44 (s, 3H), 2.40-2.29 (m, 1H), 2.26 (s, 3H),1.84-1.67 (m, 1H), 1.64 (s, 6H); LCMS (M+H)=499.4; HPLC RT=9.35 min(Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min; Flow:0.5 mL/min; Detection: UV at 220 nm). SFC RT=8.36 min (Column: ChiralpakIC, 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min).Enantiomer B: ¹H NMR (400 MHz, CD₃OD) δ 8.89 (d, J=1.1 Hz, 1H), 8.43 (d,J=1.5 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 7.84 (d, J=14.5 Hz,2H), 7.53 (dd, J=8.4, 1.3 Hz, 1H), 6.21 (dd, J=11.2, 4.4 Hz, 1H),3.02-2.88 (m, 1H), 2.82-2.72 (m, 1H), 2.44 (s, 3H), 2.39-2.29 (m, 1H),2.26 (s, 3H), 1.82-1.68 (m, 1H), 1.64 (s, 6H); LCMS (M+H)=499.3; HPLCRT=9.28 min (Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min; Flow:0.5 mL/min; Detection: UV at 220 nm); SFC RT=12.41 min (Column:Chiralpak IC, 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2mL/min).

Examples 38 & 394-[7-Methanesulfonyl-5-(4,4,4-trifluoro-1-phenylbutyl)-5H-pyrido[3,2-b]indol-3-yl]-3,5-dimethyl-1,2-oxazole

Racemic4-[7-methanesulfonyl-5-(4,4,4-trifluoro-1-phenylbutyl)-5H-pyrido[3,2-b]indol-3-yl]-3,5-dimethyl-1,2-oxazolewas prepared according to the procedures described for Example 1,substituting (3-(methylsulfonyl)phenyl)boronic acid (CombiBlocks) for(3-(methoxycarbonyl)phenyl)boronic acid in Step 2. Separation usingchiral prep SFC gave Enantiomers A and B. Enantiomer A: ¹H NMR (500 MHz,CDCl₃) δ 8.63 (d, J=8.2 Hz, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.17 (s, 1H),7.95 (dd, J=8.2, 1.4 Hz, 1H), 7.42-7.32 (m, 4H), 7.28 (d, J=1.7 Hz, 2H),6.06 (dd, J=10.9, 5.1 Hz, 1H), 3.17 (s, 3H), 2.98-2.89 (m, 1H), 2.81(ddt, J=19.7, 10.6, 5.2 Hz, 1H), 2.33 (s, 3H), 2.25-2.16 (m, 1H), 2.15(s, 3H), 1.88-1.76 (m, 1H); LCMS (M+H)=528.3; HPLC RT=2.87 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFC RT=10.03 min(Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH;Flow: 2 mL/min); [α]_(D) ²⁰=−56.9 (c=0.12, CHCl₃). Enantiomer B: ¹H NMR(500 MHz, CDCl₃) δ 8.63 (d, J=8.2 Hz, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.17(s, 1H), 7.95 (dd, J=8.2, 1.4 Hz, 1H), 7.42-7.32 (m, 4H), 7.28 (d, J=1.7Hz, 2H), 6.06 (dd, J=10.9, 5.1 Hz, 1H), 3.17 (s, 3H), 2.98-2.89 (m, 1H),2.81 (ddt, J=19.7, 10.6, 5.2 Hz, 1H), 2.33 (s, 3H), 2.25-2.16 (m, 1H),2.15 (s, 3H), 1.88-1.76 (m, 1H); LCMS (M+H)=528.3; HPLC RT=2.87 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFCRT=19.50 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:75/25 CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=+62.7 (c=0.14, CHCl₃).

Examples 40 & 412-{5-[(4-Fluorophenyl)(oxan-4-yl)methyl]-3-(5-methyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate

To a mixture of 2,5-dibromo-3-nitropyridine (2.00 g, 7.09 mmol),(4-(methoxycarbonyl)phenyl)boronic acid (1.28 g, 7.09 mmol) Pd(dppf)Cl₂(0.36 g, 0.50 mmol) in THF (30 mL) was added tripotassium phosphate (3Min water) (7.09 mL, 21.3 mmol). The reaction mixture was purged with N₂(3×) and then stirred at 80° C. for 3 h. The aqueous layer wasseparated. The organic layer dried with Na₂SO₄, filtered through a smallplug of Celite® washing with EtOAc and concentrated. The crude residuewas purified using ISCO silica gel chromatography (120 g column,gradient from 0% to 50% EtOAc/CH₂Cl₂) to give the title compound (1.64g, 69%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (d, J=2.0 Hz,1H), 8.88 (d, J=2.2 Hz, 1H), 8.17-8.02 (m, 2H), 7.78-7.63 (m, 2H), 3.90(s, 3H).

Step 2: Methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate (1.64 g,4.86 mmol) and 1,2-bis(diphenylphosphino)ethane (2.42 g, 6.08 mmol) in1,2-dichlorobenzene (30 mL) was purged with N₂ (3×) and then warmed toreflux. After 4 h, the mixture was cooled to room temperature andconcentrated. The residue was suspended in CHCl₃, sonicated and thenfiltered. The solid was washed with CHCl₃ and dried to give the titlecompound (0.84 g, 57%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.85 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.29 (dd, J=5.1, 3.1 Hz, 2H),8.22 (s, 1H), 7.88 (dd, J=8.3, 1.4 Hz, 1H), 3.93 (s, 3H); LCMS(M+H)=305.1.

Step 3: Methyl3-bromo-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in Step 4 Example 1,methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (840 mg, 2.75 mmol)and (4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (Step 1 ofExample 25, 868 mg, 4.13 mmol) was converted to the title compound as aracemate (1.26 g, 92%), which was used without further purification inthe subsequent step. LCMS (M+H)=497.2.

Step 4: Methyl5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a mixture of methyl3-bromo-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(500 mg, 1.01 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (306 mg,1.21 mmol), Pd(dppf)Cl₂ (37 mg, 0.050 mmol) and KOAc (197 mg, 2.01 mmol)in a screw cap vial was added dioxane (10 mL). The vial was fitted witha teflon lined septum cap and purged with N₂ (3×). The reaction mixturewas heated at 90° C. for 16 h, then cooled to room temperature andfiltered. The filtrate was purified using ISCO silica gel chromatography(40 g column, gradient from 0% to 90% EtOAc/CH₂Cl₂) to give the titlecompound (254 mg, 46%). LCMS (M+H)=463.4.

Step 5: Methyl5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(5-methylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a screw top vial was added methyl5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(125 mg, 0.23 mmol), 4-iodo-5-methylisoxazole (48 mg, 0.23 mmol),Pd(dppf)Cl₂ (8 mg, 0.011 mmol) and phosphoric acid, potassium salt (0.23mL, 0.69 mmol) followed by THF (1.5 mL). The resulting suspension washeated at 80° C. for 45 min, then cooled to room temperature, dilutedwith EtOAc and quenched with water. The organic layer was washed withwater, sat. NaCl, dried and concentrated in vacuo. The crude product waspurified using ISCO silica gel chromatography (24 g column, gradientfrom 0% to 100% EtOAc/CH₂Cl₂) to give the title compound (83 mg, 72%).LCMS (M+H)=500.1; HPLC RT=3.68 min (Column: Waters Sunfire C18 5 μm,2.1×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Gradient 0-100% B over 4 min; Flow: 1mL/min; Detection: UV at 220 nm).

Step 6:2-{5-[(4-Fluorophenyl)(oxan-4-yl)methyl]-3-(5-methyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described in Step 5 Example 1,methyl5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(5-methylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(105 mg, 0.21 mmol) was converted to racemic2-{5-[(4-fluorophenyl)(oxan-4-yl)methyl]-3-(5-methyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(60 mg, 57%) which was separated by chiral prep SFC to give EnantiomersA and B. Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 1H), 8.52 (d,J=1.8 Hz, 1H), 8.34-8.13 (m, 2H), 8.05 (s, 1H), 7.79-7.62 (m, 2H), 7.46(dd, J=8.4, 1.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 2H), 5.76 (d, J=11.0 Hz,1H), 4.19-3.75 (m, 3H), 3.68-3.54 (m, 1H), 3.50-3.35 (m, 2H), 2.64 (s,2H), 2.08-1.86 (m, 1H), 1.86-1.74 (m, 1H), 1.74-1.53 (m, 6H), 1.53-0.99(m, 4H); LCMS (M+H)=500.5; SFC RT=7.68 (Column: Chiralcel OD-H 250×4.6mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min); [α]_(D)²⁰=−79.08 (c=0.11, MeOH). Enantiomer B: ¹H NMR (400 MHz, CD₃OD) δ 8.75(s, 1H), 8.52 (d, J=1.5 Hz, 1H), 8.26 (s, 2H), 8.12-7.90 (m, 1H),7.81-7.60 (m, 2H), 7.58-7.34 (m, 1H), 7.10 (s, 2H), 5.88-5.64 (m, 1H),4.15-3.74 (m, 3H), 3.72-3.55 (m, 1H), 3.37 (s, 2H), 2.64 (s, 2H),2.10-1.90 (m, 1H), 1.68 (d, J=3.7 Hz, 6H), 1.51-1.26 (m, 2H), 1.25-1.01(m, 2H); LCMS (M+H)=500.5; SFC RT=10.51 (Column: Chiralcel OD-H 250×4.6mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min).

Examples 42 & 432-{5-[(4-Fluorophenyl)(oxan-4-yl)methyl]-3-(3-methyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Racemic2-{5-[(4-fluorophenyl)(oxan-4-yl)methyl]-3-(3-methyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,was prepared according to the procedures described for Example 40,substituting 4-bromo-3-methylisoxazole [Gibson, C. et al. J. Med. Chem.2009, 52, 4370-4279] for 4-iodo-5-methylisoxazole in Step 5. Separationusing chiral prep SFC gave Enantiomers A and B. Enantiomer A: ¹H NMR(400 MHz, CD₃OD) δ 8.96 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.40-8.16 (m,2H), 8.05 (s, 1H), 7.68 (dd, J=8.6, 5.3 Hz, 2H), 7.47 (dd, J=8.4, 1.3Hz, 1H), 7.10 (t, J=8.8 Hz, 2H), 5.76 (d, J=11.0 Hz, 1H), 4.18-3.76 (m,3H), 3.37 (s, 4H), 2.46 (s, 3H), 2.39-2.21 (m, 1H), 1.68 (d, J=3.7 Hz,11H), 1.46-0.95 (m, 3H); LCMS (M+H)=500.5; SFC RT=7.92 (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2mL/min); [α]_(D) ²⁰=−25.54 (c=0.35, CHCl₃). Enantiomer B: ¹H NMR (400MHz, CD₃OD) δ 8.96 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.40-8.16 (m, 2H),8.05 (s, 1H), 7.68 (dd, J=8.6, 5.3 Hz, 2H), 7.47 (dd, J=8.4, 1.3 Hz,1H), 7.10 (t, J=8.8 Hz, 2H), 5.76 (d, J=11.0 Hz, 1H), 4.18-3.76 (m, 3H),3.37 (s, 4H), 2.46 (s, 3H), 2.39-2.21 (m, 1H), 1.68 (d, J=3.7 Hz, 11H),1.46-0.95 (m, 3H); LCMS (M+H)=500.5; SFC RT=10.45 (Column: ChiralcelOD-H 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min).

Example 443-(Dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylicacid

To a 5 mL vial containing methyl3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(Step 4 of Example 1, 54 mg, 0.11 mmol) in MeOH (2.0 mL) was added 1NNaOH (1.10 mL, 1.10 mmol). The resulting reaction mixture was heated at80° C. for 30 min and then concentrated. 1M citric acid (1.10 mL, 1.10mmol) was added, and the white solid was collected via filtration,rinsed with water and dried under vacuum to give the title compound as aracemate (17 mg, 31%). ¹H NMR (500 MHz, CDCl₃) δ 8.57-8.47 (m, 3H), 8.15(dd, J=8.3, 1.1 Hz, 1H), 7.63 (d, J=1.4 Hz, 1H), 7.48 (d, J=7.5 Hz, 2H),7.40-7.34 (m, 2H), 7.31 (d, J=7.2 Hz, 1H), 5.62 (d, J=10.5 Hz, 1H),4.13-4.04 (m, 1H), 3.92-3.81 (m, 1H), 3.62-3.52 (m, 1H), 3.42-3.33 (m,1H), 3.14 (q, J=10.9 Hz, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.05 (d,J=13.0 Hz, 1H), 1.69-1.63 (m, 1H), 1.48-1.40 (m, 1H), 1.12 (d, J=13.3Hz, 1H); LCMS (M+H)=482.1; HPLC RT=2.74 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Example 453-(Dimethyl-1,2-oxazol-4-yl)-5-(diphenylmethyl)-5H-pyrido[3,2-b]indole-7-carboxylicacid

Following a procedure analogous to that described for Example 44, methyl5-benzhydryl-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(Step 4 of Example 3, 17 mg, 0.035 mmol) was converted to the titlecompound (14 mg, 84%). ¹H NMR (500 MHz, CDCl₃) δ 8.57-8.48 (m, 2H), 8.26(s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.42-7.34 (m, 6H), 7.31 (s, 1H),7.25-7.19 (m, 4H), 6.96 (d, J=1.7 Hz, 1H), 2.25 (s, 3H), 2.07 (s, 3H);LCMS (M+H)=474.0; HPLC RT=3.11 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 462-[5-Benzyl-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl5-benzyl-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a 5 mL vial containing methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (Step3 of Example 1, 39 mg, 0.12 mmol) and K₂CO₃ (50 mg, 0.36 mmol) in DMF(0.5 mL) was added benzyl bromide (0.021 mL, 0.18 mmol). The resultingreaction mixture was heated at 70° C. for 1 h. Additional benzyl bromide(0.021 mL, 0.18 mmol) was added and heating was continued at 70° C. for10 min and then at 80° C. for 1 h. The reaction mixture was cooled toroom temperature and purified directly using ISCO silica gelchromatography (40 g column, gradient form 0% to 50% EtOAc/CH₂Cl₂) togive the title compound (36 mg, 74%) as a yellow solid. ¹H NMR (500 MHz,CDCl₃) δ 8.52 (d, J=1.9 Hz, 1H), 8.48 (dd, J=8.0, 0.6 Hz, 1H), 8.28 (d,J=0.6 Hz, 1H), 8.08 (dd, J=8.2, 1.2 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H),7.34-7.28 (m, 3H), 7.16 (dd, J=7.6, 1.8 Hz, 2H), 5.61 (s, 2H), 3.99 (s,3H), 2.39 (s, 3H), 2.22 (s, 3H); LCMS (M+H)=412.1; HPLC RT=3.03 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2:2-[5-Benzyl-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described in Step 5 of Example1, methyl5-benzyl-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(36 mg, 0.087 mmol) was converted to the title compound (2 mg, 4%) afterpurification by prep HPLC (Column: Phen Luna C18, 30×100 mm, 5 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; MobilePhase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 10-100% B over12 min, then a 2-min hold at 100% B; Flow: 40 mL/min). ¹H NMR (500 MHz,CDCl₃) δ 8.45 (d, J=1.7 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 7.74 (s, 1H),7.45 (dd, J=8.3, 1.4 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.34-7.29 (m, 4H),7.19-7.15 (m, 2H), 5.57 (s, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 1.70 (s,6H); LCMS (M+H)=412.1; HPLC RT=2.42 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Examples 47-49

The compounds in Table 2 were prepared according to the proceduresdescribed for Example 46:

TABLE 2 HPLC RT LCMS HPLC Example X (min) (M + H) Method 47

1.94 420.4 A 48

2.41 430.4 A 49

2.40 454.5 A

HPLC Conditions for Table 2:

Method A:

-   -   Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90        MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with        0.1% TFA;    -   Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4        mL/min; Detection: UV at 220 nm.

Example 504-[5-Benzyl-7-(difluoromethyl)-5H-pyrido[3,2-b]indol-3-yl]-3,5-dimethyl-1,2-oxazole

Step 1:3-((2-Chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)benzaldehyde

To a 100 mL round bottom flask containing2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine (Step 1 of Example1, 1.00 g, 4.47 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(X-phos precatalyst, 0.21 g, 0.27 mmol) and 3-bromobenzaldehyde (1.56mL, 13.4 mmol) in toluene (20 mL) was added cesium carbonate (2.91 g,8.94 mmol). The reaction mixture was heated at 100° C. for 16 h, thencooled to room temperature and diluted with EtOAc (100 mL). Filtrationthrough Celite® and concentration gave a crude residue which waspurified using ISCO silica gel chromatography (24 g column, gradientfrom 0% to 100% EtOAc/hexanes) to give the title compound (359 mg, 24%).LCMS (M+H)=328.1; HPLC RT=1.63 min (Column: Waters Acquity BEH C18,2.0×50 mm, 1.7 μm particles; Mobile Phase A: 10:90 acetonitrile:waterwith 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min, then a 0.75-minhold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm)

Step 2:3-(3,5-Dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carbaldehyde

To a 5 mL microwave vial containing3-((2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)benzaldehyde(359 mg, 1.10 mmol) and sodium acetate (225 mg, 2.74 mmol) in DMA (5.0mL) was added bis(triphenylphosphine)palladium(II) chloride (62 mg,0.088 mmol). The resulting suspension was heated at 170° C. in amicrowave reactor for 20 min, then at 180° C. for 20 min, then at 200°C. for 40 min. The reaction mixture was purified directly using ISCOsilica gel chromatography (24 g column, gradient from 0% to 100%EtOAc/hexanes) to give the title compound (69 mg, 22%). LCMS(M+H)=292.2; HPLC RT=0.88 min (Column: Waters Acquity BEH C18, 2.0×50mm, 1.7 μm particles; Mobile Phase A: 10:90 acetonitrile:water with 0.1%TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min, then a 0.75-minhold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm)

Step 3:5-Benzyl-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carbaldehyde

To a 25 mL round bottom flask containing3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carbaldehyde (22mg, 0.076 mmol) and cesium carbonate (98 mg, 0.30 mmol) in DMF (1.0 mL)was added benzyl bromide (0.018 mL, 0.15 mmol). The resulting suspensionwas stirred at room temperature for 3 h and then concentrated. The crudeproduct was purified using ISCO silica gel chromatography (4 g column,gradient from 0% to 100% EtOAc/hexanes) to give the title compound (9mg, 31%). LCMS (M+H)=382.2; HPLC RT=1.18 min (Column: Waters Acquity BEHC18, 2.0×50 mm, 1.7 μm particles; Mobile Phase A: 10:90acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 1.5 min, then a 0.75-min hold at 100% B; Flow: 1 mL/min;Detection: UV at 220 nm)

Step 4:4-[5-Benzyl-7-(difluoromethyl)-5H-pyrido[3,2-b]indol-3-yl]-3,5-dimethyl-1,2-oxazole

To a 25 mL round bottom flask containing5-benzyl-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carbaldehyde(9 mg, 0.024 mmol) in CH₂Cl₂ (2.0 mL) was added deoxofluor (104 mg, 0.24mmol). The resulting reaction mixture was stirred at room temperatureunder nitrogen overnight and then concentrated under reduced pressure.The crude material was purified via preparative LC-MS (Column: WatersXBridge C18, 19×200 mm, 5 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min) to give the titlecompound (1 mg, 14%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.40 (d,J=8.1 Hz, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.53 (d, J=8.1 Hz, 1H),7.36-7.20 (m, 6H), 5.83 (s, 2H), 2.47 (s, 3H), 2.29 (s, 3H); LCMS(M+H)=404.3; HPLC RT=1.98 min (Column: Waters Acquity UPLC BEH C18,2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% Bover 3 min, then a 0.75-min hold at 100% B; Flow: 1.11 mL/min;Detection: UV at 220 nm).

Example 514-(5-Benzyl-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethyl-1,2-oxazole

Step 1: 2-Chloro-5-(3,5-dimethylisoxazol-4-yl)-N-phenylpyridin-3-amine

Following a procedure analogous to that described in Step 1 of Example50, 2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine (Step 1 ofExample 1, 0.50 g, 2.24 mmol) and bromobenzene (1.05 g, 6.71 mmol) wereconverted to the title compound (200 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆)δ 7.98 (s, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H),7.36-7.28 (m, 2H), 7.22 (d, J=7.5 Hz, 2H), 7.02 (t, J=7.3 Hz, 1H), 2.40(s, 3H), 2.21 (s, 3H); LCMS (M+H)=300.2; HPLC RT=1.23 min (Column:Waters Acquity BEH C18, 2.0×50 mm, 1.7 μm particles; Mobile Phase A:10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 1.5 min, then a 0.75-min hold at 100% B; Flow: 1 mL/min;Detection: UV at 220 nm).

Step 2: 3,5-Dimethyl-4-(5H-pyrido[3,2-b]indol-3-yl)isoxazole

Following a procedure analogous to that described in Step 2 of Example50, 2-chloro-5-(3,5-dimethylisoxazol-4-yl)-N-phenylpyridin-3-amine (200mg, 0.67 mmol) was converted to the title compound (73 mg, 42%). ¹H NMR(400 MHz, DMSO-d₆) δ 11.51 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.21 (d,J=7.9 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.57-7.50 (m,1H), 7.28 (td, J=7.4, 1.1 Hz, 1H), 2.49 (s, 3H), 2.30 (s, 3H); LCMS(M+H)=264.2; HPLC RT=0.84 min (Column: Waters Acquity BEH C18, 2.0×50mm, 1.7 μm particles; Mobile Phase A: 10:90 acetonitrile:water with 0.1%TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min, then a 0.75-minhold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm).

Step 3: 4-(5-Benzyl-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethyl-1,2-oxazole

Following a procedure analogous to that described in Step 1 of Example46, 3,5-dimethyl-4-(5H-pyrido[3,2-b]indol-3-yl)isoxazole (73 mg, 0.28mmol) was converted to the title compound (51 mg, 52%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.55 (s, 1H), 8.30 (d, J=7.7 Hz, 1H), 8.24 (s, 1H), 7.80 (d,J=8.4 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.31-7.18(m, 5H), 5.77 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H); LCMS (M+H)=354.2;HPLC RT=1.98 min (Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm).

Example 524-(5-Benzyl-7-(methylsulfonyl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethyl-1,2-oxazole

Step 1:2-Chloro-5-(3,5-dimethylisoxazol-4-yl)-N-(3-(methylsulfonyl)phenyl)pyridin-3-amine

Following a procedure analogous to that described in Step 2 of Example1, 2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine (Step 1 ofExample 1, 284 mg, 1.27 mmol) and (3-(methylsulfonyl)phenyl)boronic acid(CombiBlocks, 533 mg, 2.67 mmol) were converted to the title compound(100 mg, 21%). LCMS (M+H)=378.3; HPLC RT=2.08 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Step 2:4-(5-Benzyl-7-(methylsulfonyl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethyl-1,2-oxazole

Following procedures analogous to those described in Steps 2 and 3 ofExample 50,2-chloro-5-(3,5-dimethylisoxazol-4-yl)-N-(3-(methylsulfonyl)phenyl)pyridin-3-amine(99 mg, 0.26 mmol) was converted to the title compound (23 mg, 20% overtwo steps). ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=8.2 Hz, 1H), 8.57 (d,J=1.7 Hz, 1H), 8.17 (d, J=1.0 Hz, 1H), 7.93 (dd, J=8.3, 1.4 Hz, 1H),7.49 (d, J=1.7 Hz, 1H), 7.38-7.30 (m, 3H), 7.15 (dd, J=7.2, 2.2 Hz, 2H),5.63 (s, 2H), 3.16 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H); LCMS(M+H)=432.4; HPLC RT=2.55 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 532-[5-Benzyl-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-9-yl]propan-2-ol

Step 1: 5-(3,5-Dimethylisoxazol-4-yl)pyridin-3-amine

To a 40 mL vial containing 5-bromopyridin-3-amine (Aldrich, 200 mg, 1.16mmol) and3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(Aldrich, 516 mg, 2.31 mmol) in THF (10 mL) was added aq. tripotassiumphosphate (2M, 1.7 mL, 3.47 mmol) to give a yellow suspension.Pd(dppf)Cl₂—CH₂Cl₂ (94 mg, 0.12 mmol) was then added and N₂ was bubbledinto the mixture for 2 min. The resulting reaction mixture was heated at80° C. for 1 h, concentrated and purified using ISCO silica gelchromatography (40 g column, gradient from 0% to 10% MeOH/CH₂Cl₂) togive the title compound (213 mg, 97%) as a pale orange solid. LCMS(M+H)=190; HPLC RT=0.51 min (Column: Chromolith ODS S5 4.6×50 mm; MobilePhase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 2: Methyl3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)benzoate

To a 40 mL pressure vial containing5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine (212 mg, 1.12 mmol), methyl3-bromobenzoate (Lancaster, 241 mg, 1.12 mmol) and Cs₂CO₃ (730 mg, 2.24mmol) in toluene (10 mL) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(88 mg, 0.11 mmol). N₂ was bubbled through the reaction mixture for 1min. The vial was sealed and heated to 100° C. for 16 h. After coolingto room temperature, the mixture was concentrated and purified usingISCO silica gel chromatography (80 g column, gradient from 0% to 100%EtOAc/CH₂Cl₂) to give the title compound (130 mg, 36%) as a white solid.¹H NMR (500 MHz, CDCl₃) δ 8.37 (d, J=2.5 Hz, 1H), 8.13 (d, J=1.9 Hz,1H), 7.89-7.79 (m, 1H), 7.70 (dt, J=7.6, 1.2 Hz, 1H), 7.41 (t, J=7.9 Hz,1H), 7.34-7.31 (m, 1H), 7.28 (dd, J=2.4, 1.0 Hz, 1H), 5.90 (s, 1H), 3.92(s, 3H), 2.46 (s, 3H), 2.32 (s, 3H); LCMS (M+H)=324; HPLC RT=1.90 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 3: Methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-9-carboxylate

A 40 mL pressure vial containing methyl3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)benzoate (130 mg,0.40 mmol), palladium (II) acetate (18 mg, 0.08 mmol) and K₂CO₃ (11.1mg, 0.08 mmol) in pivalic acid (2 mL) was heated open to air at 110° C.for 12 h. After cooling to room temperature, the mixture was dilutedwith MTBE (6 mL), and the precipitate was filtered with MTBE rinses. Ina 40 mL pressure vial, the solid was dissolved in TFA (3 mL) andpalladium (II) acetate (18.1 mg, 0.08 mmol) was added. The vial wassealed and heated at 100° C. for 15 h. After cooling to roomtemperature, additional palladium (II) acetate (18 mg, 0.08 mmol) wasadded. The reaction was capped and heated for another 24 h. Aftercooling to room temperature, the reaction was concentrated and purifiedusing preparative HPLC (Luna C18 30×100 column, 12 min gradient from 10%B to 100% B) to give the title compound (4 mg, 3%) as a yellow solid. ¹HNMR (500 MHz, CD₃OD) δ 8.85 (d, J=1.7 Hz, 1H), 8.78 (d, J=1.7 Hz, 1H),8.32 (dd, J=7.5, 0.8 Hz, 1H), 8.17 (dd, J=8.5, 0.7 Hz, 1H), 7.98 (dd,J=8.5, 7.6 Hz, 1H), 4.21 (s, 3H), 2.58 (s, 3H), 2.40 (s, 3H); LCMS(M+H)=322; HPLC RT=1.78 min (Column: Chromolith ODS S5 4.6×50 mm; MobilePhase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 4: Methyl5-benzyl-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-9-carboxylate

Following a procedure analogous to that described in Step 1 of Example46, methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-9-carboxylate (4mg, 0.012 mmol) was converted to the title compound (4 mg, 76%). ¹H NMR(500 MHz, CDCl₃) δ 8.61 (d, J=1.9 Hz, 1H), 7.75 (dd, J=7.2, 1.1 Hz, 1H),7.67-7.62 (m, 1H), 7.61-7.55 (m, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.35-7.27(m, 3H), 7.11 (dd, J=7.4, 2.1 Hz, 2H), 5.59 (s, 2H), 4.15 (s, 3H), 2.38(s, 3H), 2.21 (s, 3H).

Step 5:2-[5-Benzyl-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-9-yl]propan-2-ol

A 5 mL vial containing methyl5-benzyl-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-9-carboxylate(4 mg, 9.5 μmol) in THF (0.2 mL) was cooled to −78° C. and MeLi (1.6M inEt₂O, 36 μL, 57 μmol) was added dropwise. The resulting reaction mixturewas stirred at −78° C. for 30 min, then quenched with sat. NH₄Cl andextracted with EtOAc (2×). The organic layer was concentrated andpurified using ISCO silica gel chromatography (12 g column, gradientfrom 50% to 100% EtOAc/CH₂Cl₂) and further purified using prep HPLC(Column: Phen Luna C18, 30×100 mm, 5 μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.1% TFA; Gradient: 10-100% B over 12 min, thena 2-min hold at 100% B; Flow: 40 mL/min). The fraction containingdesired product was diluted with sat. NaHCO₃ solution and concentrated.The residue was rediluted in sat. NaHCO₃ solution and extracted withCHCl₃ (3×). The organic layer was dried over MgSO₄, filtered andconcentrated to give the title compound (2 mg, 43%). ¹H NMR (500 MHz,CDCl₃) δ 8.81 (br s, 1H), 8.42 (d, J=1.9 Hz, 1H), 7.58-7.52 (m, 1H),7.48 (d, J=1.7 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.36-7.28 (m, 4H),7.18-7.12 (m, 2H), 5.57 (s, 2H), 2.39 (s, 3H), 2.23 (s, 3H), 1.85 (s,6H); LCMS (M+H)=412.2; HPLC RT=2.73 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Examples 54 & 552-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine

To a 100 mL round bottom flask containing5-bromo-2-chloropyridin-3-amine (2.90 g, 14.0 mmol),1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (2.70 g, 6.99 mmol)[Seefeld, M. A. et al. PCT Int. Appl., 2008, WO2008098104] and Pd(PPh₃)₄(0.61 g, 0.52 mmol) in DMF (20 mL) was added cuprous iodide (0.20 g,1.05 mmol) and Et₃N (1.9 mL, 14.0 mmol). The reaction mixture was purgedwith N₂ for 3 min and then heated at 100° C. for 1 h. After cooling toroom temperature, the mixture was diluted with 10% LiCl solution andextracted with EtOAc (2×). The combined organics were washed with sat.NaCl, dried over MgSO₄, filtered and concentrated. CH₂Cl₂ was added, andthe resulting precipitate was collected by filtration. The mother liquorwas concentrated and purified using ISCO silica gel chromatography (40 gcolumn, gradient from 0% to 100% EtOAc/CH₂Cl₂). The resulting solid wascombined with the precipitate and triturated with cold EtOAc to give thetitle compound (740 mg, 47%) as a light tan solid. LCMS (M+H)=224.1;HPLC RT=1.03 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A:10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2: Methyl3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Following a procedure analogous to that described in Step 2 of Example1, 2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine (740mg, 3.31 mmol) was converted to the title compound (644 mg, 54%). ¹H NMR(400 MHz, CDCl₃) δ 7.94 (t, J=1.9 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.83(dt, J=7.8, 1.3 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H),7.36 (ddd, J=8.0, 2.3, 0.9 Hz, 1H), 6.38 (s, 1H), 3.99 (s, 3H), 3.93 (s,3H), 2.34 (s, 3H); LCMS (M+H)=358.2; HPLC RT=2.34 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in Step 3 of Example1, methyl3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate(2.82 g, 7.88 mmol) was converted to the title compound (1.58 g, 62%).¹H NMR (500 MHz, DMSO-d₆) δ 11.93 (s, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.36(dd, J=8.2, 0.6 Hz, 1H), 8.29-8.22 (m, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.91(dd, J=8.2, 1.4 Hz, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 2.31 (s, 3H); LCMS(M+H)=322.3; HPLC RT=1.98 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Alternate Synthesis of Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (Step 2of Example 40, 3.000 g, 9.83 mmol),1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (4.18 g, 10.82 mmol),copper (I) iodide (0.281 g, 1.475 mmol), Pd(Ph₃P)₄ (0.738 g, 0.639 mmol)and triethylamine (2.74 mL, 19.66 mmol) in DMF (25 mL) was purged undera nitrogen stream and then heated in a heating block at 95° C. for 2hours. After cooling to room temperature the reaction mixture wasdiluted with water and extracted into ethyl acetate. Washed with water,NH₄OH, brine and concentrated. The residue was triturated with 100 mLCHCl₃, filtered off the solid and rinsed with CHCl₃ to give. 1.6 g ofproduct. The filtrate was loaded unto the ISCO column (330 g column, A:DCM; B: 10% MeOH/DCM, 0 to 100% gradient) and chromatographed to give anadditional 0.7 g. of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(2.30 g total, 7.16 mmol, 72.8% yield).

Step 4: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in Step 4 of Example1, methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(80 mg, 0.25 mmol) was converted to the title compound (65 mg, 53%)after purification by prep HPLC (Column: Phen Luna C18, 30×100 mm, 5 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; MobilePhase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 10-100% B over14 min, then a 2-min hold at 100% B; Flow: 40 mL/min). ¹H NMR (400 MHz,CDCl₃) δ 8.51 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 8.47 (d, J=8.1 Hz, 1H),8.10 (dd, J=8.1, 1.1 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.46 (d, J=7.3 Hz,2H), 7.40-7.30 (m, 3H), 5.62 (d, J=10.6 Hz, 1H), 4.11-4.03 (m, 4H),3.92-3.83 (m, 4H), 3.56 (td, J=11.9, 1.8 Hz, 1H), 3.35 (td, J=11.9, 1.9Hz, 1H), 3.18-3.05 (m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.0 Hz, 1H),1.71-1.58 (m, 1H), 1.50-1.37 (m, 1H), 1.09 (d, J=12.8 Hz, 1H); LCMS(M+H)=496.3; HPLC RT=2.93 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 5:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described in Step 5 of Example1, methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(65 mg, 0.13 mmol) was converted to racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC (Column: Chiralpak IB 25×2 cm, 5μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 50 mL/min); to give Enantiomer A(24 mg, 36%) and Enantiomer B (26 mg, 38%). Enantiomer A: ¹H NMR (500MHz, CDCl₃) δ 8.44 (d, J=1.8 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 7.98 (s,1H), 7.56 (d, J=1.7 Hz, 1H), 7.47-7.41 (m, 3H), 7.37-7.32 (m, 2H),7.31-7.28 (m, 1H), 5.59 (d, J=10.5 Hz, 1H), 4.06 (dd, J=11.8, 2.8 Hz,1H), 3.90-3.84 (m, 4H), 3.55 (td, J=11.9, 2.0 Hz, 1H), 3.35 (td, J=11.9,2.0 Hz, 1H), 3.15-3.04 (m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, 1H),1.92 (s, 1H), 1.75 (s, 6H), 1.69-1.58 (m, 1H), 1.47-1.38 (m, 1H), 1.12(d, J=13.4 Hz, 1H); LCMS (M+H)=496.4; HPLC RT=2.46 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min). SFC RT=5.50 min(Column: Chiralpak IB 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/MeOH;Flow: 2 mL/min); SFC RT=1.06 min (Column: Chiralcel OD-H 250×4.6 mm, 5μm; Mobile Phase: 50/50 CO₂/(1:1 MeOH/CH3CN); Flow: 2 mL/min); [α]_(D)²⁰=−117.23 (c=0.08, CHCl₃). Enantiomer B: ¹H NMR (500 MHz, CDCl₃) δ 8.44(d, J=1.8 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 7.56 (d, J=1.7Hz, 1H), 7.47-7.41 (m, 3H), 7.37-7.32 (m, 2H), 7.31-7.28 (m, 1H), 5.59(d, J=10.5 Hz, 1H), 4.06 (dd, J=11.8, 2.8 Hz, 1H), 3.90-3.84 (m, 4H),3.55 (td, J=11.9, 2.0 Hz, 1H), 3.35 (td, J=11.9, 2.0 Hz, 1H), 3.15-3.04(m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, 1H), 1.92 (s, 1H), 1.75 (s,6H), 1.69-1.58 (m, 1H), 1.47-1.38 (m, 1H), 1.12 (d, J=13.4 Hz, 1H); LCMS(M+H)=496.4; HPLC RT=2.46 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min). SFC RT=8.30 min (Column: Chiralpak IB 250×4.6 mm,5 μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min); SFC RT=2.83 min(Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 50/50 CO₂/(1:1MeOH/CH3CN); Flow: 2 mL/min); [α]_(D) ²⁰=+88.78 (c=0.10, CHCl₃).

Alternate Synthesis of Examples 542-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

The enantiomers of phenyl(tetrahydro-2H-pyran-4-yl)methanol (2.0 g, 10.4mmol) [Orjales, A. et al. J. Med. Chem. 2003, 46, 5512-5532], wereseparated on preperative SFC. (Column: Chiralpak AD 5×25 cm, 5 μm;Mobile Phase: 74/26 CO₂/MeOH; Flow: 270 mL/min; Temperature 30° C.). Theseparated peaks were concentrated and dried under vacuum to give whitesolids. Enantiomer A: (S)-phenyl(tetrahydro-2H-pyran-4-yl)methanol:(0.91 g, 45.5%) SFC RT=2.32 min (Column: Chiralpac AD 250×4.6 mm, 5 μm;Mobile Phase: 70/30 CO₂/MeOH; Flow: 3 mL/min); Temperature 40° C.Enantiomer B: (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol. (0.92 g,46%) SFC RT=3.09 min (Column: Chiralpac AD 250×4.6 mm, 5 μm; MobilePhase: 70/30 CO₂/MeOH; Flow: 3 mL/min); Temperature 40° C.

Following a procedure analogous to that described in Step 4 of Example 1except using toluene (120 mL) as the solvent, methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(4 g, 12.45 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(Enantiomer B above, 5.86 g, 30.5 mmol) was converted to the titlecompound (5.0 g, 81%). HPLC RT=2.91 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Step 2.(S)-2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

A 500 mL round bottom flask containing (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(5.0 g, 10.09 mmol) in THF (150 mL) was cooled in an ice/MeOH bath.MeMgBr, (3M in Et₂O, 17.0 mL, 51.0 mmol) was added slowly over 4 min.The resulting solution was stirred for 2 h and then quenched carefullywith sat. NH₄Cl. The reaction mixture was diluted with 10% LiCl solutionextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated. The crude material was purified using ISCO silica gelchromatography (120 g column, gradient from 0% to 6% MeOH/CH₂Cl₂). Theproduct was collected and concentrated then dissolved in hot MeOH (35mL). To the mixture was added 15 mL water and the mixture was cooled toroom temperature. The resulting white precipitate was collected byfiltration with 2:1 MeOH/water rinse then dried under vacuum to give thetitle compound (3.2 g, 62%). ¹H NMR (500 MHz, CDCl₃) δ 8.40 (d, J=1.8Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.53 (d, J=1.8 Hz, 1H),7.46 (d, J=7.3 Hz, 2H), 7.42 (dd, J=8.2, 1.4 Hz, 1H), 7.37-7.31 (m, 2H),7.30-7.28 (m, 1H), 5.56 (d, J=10.5 Hz, 1H), 4.06 (d, J=8.9 Hz, 1H),3.89-3.83 (m, 1H), 3.55 (td, J=11.9, 2.1 Hz, 1H), 3.35 (td, J=11.9, 2.1Hz, 1H), 3.10 (q, J=10.8 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H), 2.03 (d,J=14.2 Hz, 1H), 1.89 (s, 1H), 1.74 (s, 6H), 1.68-1.59 (m, 1H), 1.46-1.36(m, 1H), 1.12 (d, J=12.2 Hz, 1H); LCMS (M+H)=496.3; HPLC RT=2.44 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFCRT=2.01 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:60/40 CO₂/(1:1 MeOH/CH3CN); Flow: 2 mL/min). SFC RT=1.06 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 50/50 CO₂/(1:1MeOH/CH3CN); Flow: 2 mL/min).

Examples 56-65

The compounds in Table 3 were prepared according to the proceduresdescribed for Example 54:

TABLE 3 HPLC RT LCMS Optical Rotation HPLC Example X Y (min) (M + H)[α]_(D) ²⁰ Method 56

2.67 528.4 N/A A 57 Enantiomer A

4.14 508.4 −42.34 (c = 0.14,CHCl₃) B 58 Enantiomer B

11.51 508.4 +56.43 (c = 0.09, CHCl₃) B 59 Enantiomer A

35.27 514.4 −91.54 (c = 0.09, CHCl₃) C 60 Enantiomer B

39.50 514.4 +93.98 (c = 0.06, CHCl₃) C 61

2.58 420.4 N/A A 62 Enantiomer A

7.22 497.5 N/A B 63 Enantiomer B

9.68 497.5 N/A B 64 Enantiomer A

5.13 514.4 −122.49  (c = 3.03, CHCl₃) B 65 Enantiomer B

9.35 514.4 +116.15  (c = 3.03, CHCl₃) B

HPLC Conditions for Table 3:

Method A:

-   -   Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90        MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with        0.1% TFA;    -   Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4        mL/min; Detection: UV at 220 nm.

Method B:

-   -   Column: Chiralcel OD-H 250×4.6 mm, 5 μm particles; Mobile Phase:        80/20 CO₂/MeOH; Flow: 2 mL/min; Detection: UV at 220 nm.

Method C:

-   -   Chiralpak IC 250×4.6 mm, 5 μm particles; Mobile Phase: 70/30        CO₂/MeOH; Flow: 2 mL/min; Detection: UV at 220 nm.

Examples 66 & 672-{5-[(4-Fluorophenyl)(oxan-4-yl)methyl]-3-(1-methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (244 mg,0.66 mmol) [Allgeier, H. et al., PCT Int. Appl., 2006, WO2006108591],methyl3-bromo-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(Step 3 of Example 40, 163 mg, 0.33 mmol), copper (I) iodide (9 mg, 0.05mmol), Pd(PPh₃)₄ (28 mg, 0.02 mmol) and triethylamine (0.091 mL, 0.65mmol) in DMF (2.0 mL) was purged with N₂ (3×) and then warmed to 100° C.and stirred for 2 h. After cooling to room temperature, the reactionmixture was filtered through Celite® washing with EtOAc. The filtratewas washed with 10% LiCl solution and sat. NaCl, dried over Na₂SO₄,filtered and concentrated. The residue was purified using ISCO silicagel chromatography (24 g column, gradient from 0% to 100% EtOAc/hexanes)to give the title compound (64 mg, 39%). LCMS (M+H)=500.2.

Step 2:2-{5-[(4-Fluorophenyl)(oxan-4-yl)methyl]-3-(1-methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described in Step 5 of Example1, methyl5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(65 mg, 0.13 mmol) was converted to racemic2-{5-[(4-fluorophenyl)(oxan-4-yl)methyl]-3-(1-methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (20 mg, 30%)and Enantiomer B (20 mg, 30%). Enantiomer A: ¹H NMR (400 MHz, DMSO-d₆) δ8.59 (s, 1H), 8.56-8.47 (bs, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.12-8.03 (m,2H), 7.73 (dd, J=8.6, 5.5 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.18 (t,J=8.8 Hz, 2H), 5.83 (d, J=11.2 Hz, 1H), 5.22 (s, 1H), 4.14 (s, 3H), 3.92(d, J=9.7 Hz, 1H), 3.73 (d, J=8.8 Hz, 1H), 3.56-3.35 (m, 2H), 3.27 (d,J=13.6 Hz, 1H), 1.68 (m., 1H), 1.58 (m, 7H), 1.42-1.21 (m, 1H), 0.98 (d,J=12.8 Hz, 1H); LCMS (M+H)=500.3; HPLC RT=7.29 min (Column: Sunfire C183.5 μm, 3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient0-100% B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220 nm). SFCRT=9.86 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm particles; MobilePhase: 75/25 CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=−99.55 (c=0.14,CHCl₃). Enantiomer B: ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H),8.56-8.46 (bs, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.03-8.11 (m, 2H), 7.73 (dd,J=8.6, 5.5 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 7.18 (t, J=8.8 Hz, 2H), 5.83(d, J=11.2 Hz, 1H), 5.22 (s, 1H), 4.14 (s, 3H), 4.01-3.84 (m, 1H),3.81-3.66 (m, 1H), 3.49 (s, 2H), 3.30-3.18 (m, 1H), 1.82-1.65 (m, 1H),1.58 (m, 7H, overlapping 2CH3 and 1CH), 1.40-1.21 (m, 1H), 1.10-0.89 (m,1H); LCMS (M+H)=500.3; HPLC RT=7.28 min (Column: Sunfire C18 3.5 μm,3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100%B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220 nm). SFC RT=12.09min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm particles; Mobile Phase:75/25 CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=+98.84 (c=0.14, CHCl₃).

Example 692-[5-Benzyl-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Example 46, methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(Step 3 of Example 54, 58 mg, 0.18 mmol) was converted to the titlecompound (57 mg, 78% over 2 steps). ¹H NMR (500 MHz, CDCl₃) δ 8.49 (d,J=1.8 Hz, 1H), 8.40 (d, J=8.2 Hz, 1H), 7.78 (d, J=0.9 Hz, 1H), 7.48 (dd,J=8.2, 1.5 Hz, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.35-7.29 (m, 3H), 7.16 (dd,J=0.7, 1.8 Hz, 2H), 5.59 (s, 2H), 3.89 (s, 3H), 2.29 (s, 3H), 1.87 (s,1H), 1.71 (s, 6H); LCMS (M+H)=412.4; HPLC RT=2.33 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Examples 70 & 712-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)-2-fluorobenzoate

To a 70 mL pressure vial containing2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine (Step 1of Example 54, 500 mg, 2.24 mmol), methyl 3-bromo-2-fluorobenzoate(Oakwood, 781 mg, 3.35 mmol) and Cs₂CO₃ (728 mg, 2.24 mmol) in dioxane(10 mL) was added 1,1′-bis(diphenylphosphino)ferrocene (62.0 mg, 0.11mmol), Pd(OAc)₂ (85 mg, 0.38 mmol) and Xantphos (65 mg, 0.11 mmol). N₂was bubbled through the reaction mixture for 2 min. The vial was sealedand heated to 100° C. for 24 h. BrettPhos precatalyst (100 mg, 0.12mmol) and additional methyl 3-bromo-2-fluorobenzoate (781 mg, 3.35 mmol)were added. N₂ was bubbled through the reaction mixture for 2 min, andthen heating was continued at 110° C. for 24 h. Additional BrettPhosprecatalyst (100 mg, 012 mmol) was added and stirring was continued at120° C. for 5 h. BrettPhos precatalyst (100 mg, 0.12 mmol) was againadded and the reaction mixture was heated at 120° C. for 5 h. Aftercooling to room temperature, the mixture was diluted with CHCl₃ andfiltered through Celite® rinsing with CHCl₃. The filtrate wasconcentrated and purified using ISCO silica gel chromatography (40 gcolumn, gradient from 0% to 100% EtOAc/CH₂Cl₂) to give the titlecompound (140 mg, 17%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.90(d, J=2.1 Hz, 1H), 7.74 (ddd, J=8.0, 6.5, 1.7 Hz, 1H), 7.52-7.44 (m,1H), 7.24 (d, J=0.9 Hz, 1H), 7.17 (t, J=2.0 Hz, 1H), 6.34 (s, 1H), 3.97(d, J=0.7 Hz, 6H), 2.32 (s, 3H); LCMS (M+H)=376.3; HPLC RT=2.23 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 3, 4 and 5 ofExample 1, methyl3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)-2-fluorobenzoate(139 mg, 0.37 mmol) was converted to racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (28 mg, 15%over 3 steps) and Enantiomer B (27 mg, 14% over 3 steps). Enantiomer A:¹H NMR (500 MHz, CDCl₃) δ 8.44 (d, J=1.7 Hz, 1H), 8.15 (d, J=8.2 Hz,1H), 7.63 (dd, J=8.2, 6.7 Hz, 1H), 7.54-7.47 (m, 3H), 7.40-7.34 (m, 2H),7.31 (d, J=7.3 Hz, 1H), 6.15 (br. s., 1H), 4.06 (dd, J=11.6, 2.3 Hz,1H), 3.89 (dd, J=11.5, 2.1 Hz, 1H), 3.81 (s, 3H), 3.56 (td, J=11.9, 2.1Hz, 1H), 3.39-3.28 (m, 1H), 3.03 (d, J=7.0 Hz, 1H), 2.26 (s, 3H), 2.23(d, J=2.4 Hz, 1H), 2.11-2.03 (m, 1H), 1.85 (d, J=2.7 Hz, 6H), 1.68-1.60(m, 1H), 1.53-1.47 (m, 1H), 1.02 (d, J=13.3 Hz, 1H); LCMS (M+H)=514.4;HPLC RT=2.84 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A:10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min); SFC RT=9.50 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min); [α]_(D) ²⁰=−142.33(c=0.08, CHCl₃). Enantiomer B: ¹H NMR (500 MHz, CDCl₃) δ 8.44 (d, J=1.7Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.63 (dd, J=8.2, 6.7 Hz, 1H), 7.54-7.47(m, 3H), 7.40-7.34 (m, 2H), 7.31 (d, J=7.3 Hz, 1H), 6.15 (br. s., 1H),4.06 (dd, J=11.6, 2.3 Hz, 1H), 3.89 (dd, J=11.5, 2.1 Hz, 1H), 3.81 (s,3H), 3.56 (td, J=11.9, 2.1 Hz, 1H), 3.39-3.28 (m, 1H), 3.03 (d, J=7.0Hz, 1H), 2.26 (s, 3H), 2.23 (d, J=2.4 Hz, 1H), 2.11-2.03 (m, 1H), 1.85(d, J=2.7 Hz, 6H), 1.68-1.60 (m, 1H), 1.53-1.47 (m, 1H), 1.02 (d, J=13.3Hz, 1H); LCMS (M+H)=514.4; HPLC RT=2.84 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min); SFC RT=11.86 min (Column: Chiralcel OD-H250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min); [α]_(D)²⁰=+92.61 (c=0.10, CHCl₃).

Examples 72-77

The compounds in Table 4 were prepared according to the proceduresdescribed for Example 70:

TABLE 4 HPLC Optical RT LCMS Rotation HPLC Example X Y (min) (M + H)[α]_(D) ²⁰ Method 72 Enantiomer A

11.65 532.4  +89.59 (c = 0.08, CHCl₃) A 73 Enantiomer B

13.56 532.4 N/A A 74

2.93 546.4 N/A B 75

3.12 438.5 N/A B 76 Enantiomer A

5.86 532.4 −145.77 (c = 1.45, CHCl₃) C 77 Enantiomer B

7.12 532.4 +147.40 (c = 2.02, CHCl₃) C

HPLC Conditions for Table 4:

Method A:

-   -   Column: Phenomenex Lux Cellulose 2, 250×4.6 mm, 5 μm particles;        Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min; Detection UV at        220 nm.

Method B:

-   -   Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90        MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with        0.1% TFA;    -   Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4        mL/min; Detection: UV at 220 nm.

Method C:

-   -   Column: Chiralcel OD-H 250×4.6 mm, 5 μm particles; Mobile Phase:        80/20 CO₂/MeOH; Flow: 2 mL/min; Detection UV at 220 nm.

Example 78 & 792-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)-2-fluorobenzoate

Following a procedure analogous to that described for Step 1 of Example40, 2,5-dibromo-3-nitropyridine (2.28 g, 8.08 mmol) and(3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (1.60 g, 8.08 mmol)were converted the title compound (1.8 g, 63%). ¹H NMR (400 MHz, CDCl₃)δ 8.97 (d, J=2.1 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.05 (t, J=7.7 Hz,1H), 7.73-7.71 (m, 1H), 7.40 (dd, J=10.9, 1.7 Hz, 1H), 7.35 (dd, J=8.1,1.7 Hz, 1H), 3.99 (s, 3H); LCMS (M+H)=355.2; HPLC RT=2.58 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2: Methyl 3-bromo-6-fluoro-5H-pyrido[3,2-b]indole-7-carboxylateMethyl 3-bromo-8-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described for Step 2 of Example40, conversion of methyl4-(5-bromo-3-nitropyridin-2-yl)-2-fluorobenzoate (1.80 g, 5.07 mmol)generated a mixture of the title compounds, which were separated usingISCO silica gel chromatography (120 g column, gradient from 50% to 70%EtOAc/hexanes) to give methyl3-bromo-6-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate (200 mg, 12%) andmethyl 3-bromo-8-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate (240 mg,15%) as white solids. Methyl3-bromo-6-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate: ¹H NMR (400 MHz,DMSO-d₆) δ 12.43 (br. s., 1H), 8.64 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.71 (dd, J=8.3, 6.1 Hz, 1H), 3.92 (s,3H); LCMS (M+H)=323.1; HPLC RT=2.62 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min). Methyl3-bromo-8-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate: ¹H NMR (400 MHz,DMSO-d₆) δ 11.81 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz,1H), 8.11 (d, J=5.9 Hz, 1H), 8.02 (d, J=10.6 Hz, 1H), 3.91 (s, 3H); LCMS(M+H)=323.1; HPLC RT=2.56 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described for Step 1 of Example66, methyl 3-bromo-8-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate (240mg, 0.74 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole(344 mg, 0.89 mmol) [Seefeld, M. A. et al. PCT Int. Appl., 2008,WO2008098104] were converted to the title compound (115 mg, 46%). ¹H NMR(400 MHz, CD₃OD) δ 8.58 (d, J=1.7 Hz, 1H), 8.19 (d, J=5.5 Hz, 1H), 8.12(d, J=10.8 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 4.08 (s, 3H), 4.01 (s, 3H),2.38 (s, 3H); LCMS (M+H)=340.2; HPLC RT=2.13 min (Column: Chromolith ODSS5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Step 4:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 ofExample 1, methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate(115 mg, 0.34 mmol) and(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (Step 1 of Example25, 143 mg, 0.68 mmol) were converted to racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC to give Enantiomer A (10 mg, 11%)and Enantiomer B (10 mg, 11%). Enantiomer A: ¹H NMR (400 MHz, CDCl₃) δ8.46 (d, J=1.7 Hz, 1H), 8.03 (d, J=11.4 Hz, 1H), 7.99 (d, J=6.1 Hz, 1H),7.58 (d, J=1.6 Hz, 1H), 7.43 (dd, J=8.7, 5.1 Hz, 2H), 7.10-7.02 (m, 2H),5.53 (d, J=10.5 Hz, 1H), 4.07 (dd, J=11.7, 2.7 Hz, 1H), 3.94 (s, 3H),3.89 (dd, J=11.7, 2.8 Hz, 1H), 3.60-3.49 (m, 1H), 3.36 (td, J=11.9, 1.9Hz, 1H), 3.12-2.98 (m, 1H), 2.32 (s, 3H), 2.26 (d, J=2.0 Hz, 1H), 1.99(d, J=13.4 Hz, 1H), 1.81 (s, 6H), 1.69-1.55 (m, 1H), 1.48-1.35 (m, 1H),1.11 (d, J=12.8 Hz, 1H); LCMS (M+H)=532.4; HPLC RT=10.52 min (Column:Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:waterwith 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 0-100% B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220nm). SFC RT=6.71 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm particles;Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min). [α]_(D) ²⁰=−100.86(c=0.68, CHCl₃). Enantiomer B: ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=1.7Hz, 1H), 8.03 (d, J=11.4 Hz, 1H), 7.99 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.6Hz, 1H), 7.43 (dd, J=8.7, 5.1 Hz, 2H), 7.11-7.02 (m, 2H), 5.53 (d,J=10.5 Hz, 1H), 4.07 (dd, J=11.7, 2.8 Hz, 1H), 3.94 (s, 3H), 3.89 (dd,J=11.9, 2.8 Hz, 1H), 3.60-3.51 (m, 1H), 3.36 (td, J=11.9, 1.9 Hz, 1H),3.12-2.99 (m, 1H), 2.32 (s, 3H), 2.28 (d, J=2.1 Hz, 1H), 1.99 (d, J=13.7Hz, 1H), 1.81 (s, 6H), 1.68-1.55 (m, 1H), 1.49-1.36 (m, 1H), 1.11 (d,J=12.6 Hz, 1H); LCMS (M+H)=499.3; HPLC RT=10.54 min (Column: Sunfire C183.5 μm, 3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient0-100% B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220 nm); SFCRT=8.09 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm particles; MobilePhase: 75/25 CO₂/MeOH; Flow: 2 mL/min). [α]_(D) ²⁰=91.50 (c=1.58,CHCl₃).

Example 80 & 812-[3-(Dimethyl-1,2-oxazol-4-yl)-6-fluoro-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-6-fluoro-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,was prepared following procedures analogous to those described forExample 70, substituting2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine (Step 1 ofExample 1) for2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine inStep 1. Separation by chiral prep SFC gave Enantiomers A and B.Enantiomer A: ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (br s, 1H), 7.97 (d,J=8.1 Hz, 1H), 7.53-7.81 (m, 3H), 7.12-7.23 (m, 3H), 5.94 (d, J=11.0 Hz,1H), 3.88 (d, J=11.9 Hz, 1H), 3.75 (dd, J=10.5, 3.2 Hz, 1H), 3.44-3.53(m, 1H), 3.26 (dd, J=11.8, 10.0 Hz, 2H), 2.42 (br s, 3H), 2.24 (br s,3H), 1.78 (d, J=12.1 Hz, 1H), 1.67 (br s, 6H), 1.25-1.40 (m, 1H),0.98-1.09 (m, 1H); LCMS (M+H)=532.4; HPLC RT=9.36 min (Column: SunfireC18 3.5 μm, 3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 0-100% B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220nm). SFC RT=15.16 min (Column: Phenomenex Lux Cellulose 4, 250×4.6 mm, 5μm particles; Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min). EnantiomerB: ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (br s, 1H), 7.97 (d, J=8.1 Hz, 1H),7.54-7.77 (m, 3H), 7.17 (t, J=7.7 Hz, 2H), 5.94 (d, J=10.6 Hz, 1H), 3.88(d, J=9.2 Hz, 1H), 3.72-3.79 (m, 1H), 3.49 (dd, J=11.6, 10.0 Hz, 1H),3.21-3.31 (m, 1H), 2.42 (br s, 3H), 2.24 (br s, 3H), 1.78 (d, J=12.3 Hz,1H), 1.67 (br s, 6H), 1.30 (d, J=9.7 Hz, 1H), 1.03 (d, J=12.5 Hz, 1H);LCMS (M+H)=532.4; HPLC RT=9.36 min (Column: Sunfire C18 3.5 μm, 3.0×150mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile PhaseB: 95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15min; Flow: 0.5 mL/min); SFC RT=18.88 min (Column: Phenomenex LuxCellulose 4, 250×4.6 mm, 5 μm particles; Mobile Phase: 75/25 CO₂/MeOH;Flow: 2 mL/min).

Examples 82-87

The compounds in Table 5 were prepared according to the proceduredescribed for Example 80:

TABLE 5 HPLC RT LCMS Optical Rotation HPLC Example X Y (min) (M + H)[α]_(D) ²⁰ Method 82

10.18 438.3 N/A A 83

10.16 546.3 N/A A 84 Enantiomer A

3.70 594.4  −74.05 (c = 0.14, CHCl₃) B 85 Enantiomer B

4.26 594.4  +72.70 (c = 0.20, CHCl₃) B 86 Enantiomer A

6.30 560.4 −181.90 (c = 0.08, CHCl₃) B 87 Enantiomer B

7.53 560.4 +165.57 (c = 0.10, CHCl₃) B N/A: Not Applicable/Available

HPLC Conditions for Table 5:

Method A:

-   -   Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A: 5:95        acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5        acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15        min; Flow: 0.5 mL/min; Detection: UV at 220 nm.

Method B:

-   -   Column: Chiralpak IC, 250×4.6 mm, 5 μm particles; Mobile Phase:        70/30 CO₂/MeOH; Flow: 2 mL/min; Detection UV at 220 nm.

Example 88(S)-2-(3-(4-(Hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Step 1:4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-iodo-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole

A mixture of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (Aldrich, 0.85mL, 4.19 mmol), (azidomethyl)trimethylsilane (TCI, 0.560 g, 4.61 mmol),copper (I) iodide (0.88 g, 4.61 mmol), 1-bromopyrrolidine-2,5-dione(Aldrich, 0.90 g, 5.03 mmol) and DIEA (0.73 mL, 4.19 mmol) in THF (35.0mL) was stirred at room temperature overnight and then concentrated invacuo. The residue was dissolved in EtOAc, washed with 10/90 conc.NH₄OH/sat. NH₄Cl solution, water and sat. NaCl and then dried overNa₂SO₄. Filtration and concentration provided a crude oil which waspurified using ISCO silica gel chromatography (80 g column, gradientfrom 0% to 50% EtOAc/hexanes) to give the title compound (0.40 g, 22%)as an amber oil. LCMS (M+H)=426.2; ¹H NMR (400 MHz, CDCl₃) δ 4.77 (s,2H), 3.84 (s, 2H), 1.00-0.86 (m, 9H), 0.25-0.19 (m, 9H), 0.16-0.11 (m,6H).

Step 2: (S)-Methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described for Step 4 of Example1, methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (Step 2 ofExample 40, 1.00 g, 3.28 mmol) and(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (1.26 g, 6.55 mmol)[obtained after chiral SFC of racemicphenyl(tetrahydro-2H-pyran-4-yl)methanol prepared according to Orjales,A. et al. J. Med. Chem. 2003, 46, 5512-5532] were converted to the titlecompound (2.06 g) as an impure mixture, which was carried on to thesubsequent step without further purification. LCMS (M+H)=481.2.

Step 3: (S)-Methyl5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described for Step 4 of Example40, (5)-methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(800 mg, 1.67 mmol) was converted to the title compound (365 mg, 42%).LCMS (M+H)=445.4 (boronic acid).

Step 4: (S)-Methyl3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A vial containing a mixture of (5)-methyl5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(360 mg, 0.68 mmol),4-(((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole(393 mg, 0.92 mmol) PdCl₂dppf (25 mg, 0.034 mmol) and aq. potassiumphosphate tribasic (3M, 0.68 mL, 2.05 mmol) in THF (5 mL) was vacuumpurged with N₂ (3×). The resulting mixture was warmed to 80° C., stirredfor 1 h and then cooled to room temperature. The mixture was dilutedwith EtOAc, transferred to a reparatory funnel, washed with water andsat. NaCl, and dried over Na₂SO₄. Filtration and concentration provideda crude oil which was purified using ISCO silica gel chromatography (40g column, gradient from 0% to 100% EtOAc/hexanes) to give the titlecompound (277 mg, 58%). LCMS (M+H)=698.6.

Step 5:(S)-2-(3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Following a procedure analogous to that described for Step 5 of Example1, (5)-methyl3-(4-4(tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(270 mg, 0.39 mmol) was converted to the title compound (212 mg, 79%).LCMS (M+H)=698.7.

Step 6:(S)-2-(3-(4-(Hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

TBAF (1M in THF, 0.74 mL, 0.74 mmol) was added to a 0° C. solution of(S)-2-(3-(44(tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol,(208 mg, 0.30 mmol) in THF (3.0 mL) and water (11 μL, 0.60 mmol). Theresulting reaction mixture was stirred at 0° C. for 30 min. AdditionalTBAF (1M in THF, 0.74 mL, 0.74 mmol) was added and stirring wascontinued at room temperature for 1 h. TBAF (1M in THF, 0.74 mL, 0.74mmol) was again added, and after stirring for 1 h the reaction mixturewas quenched with sat. NH₄Cl and transferred to a separatory funnel. Theaqueous layer was extracted with EtOAc (2×). The combined extracts werewashed with sat. NH₄Cl, water and sat. NaCl, and then dried over Na₂SO₄.Filtration and concentration gave a residue which was purified usingISCO silica gel chromatography (24 g column, gradient from 0% to 10%MeOH/CH₂Cl₂) to give the title compound (128 mg, 78%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.64 (d, J=1.8 Hz, 1H), 8.54 (br s, 1H), 8.15 (d, J=8.4 Hz,2H), 7.67 (d, J=7.3 Hz, 2H), 7.53-7.45 (m, 1H), 7.39-7.30 (m, 2H), 7.26(d, J=7.3 Hz, 1H), 5.79 (d, J=11.2 Hz, 1H), 5.37 (t, J=5.2 Hz, 1H), 5.23(s, 1H), 4.54 (t, J=4.6 Hz, 2H), 4.07 (s, 3H), 3.89 (br s, 1H), 3.74 (brs, 1H), 3.45 (d, J=13.0 Hz, 2H), 3.29 (br s, 1H), 1.67 (br s, 1H), 1.59(m, 7H), 1.40-1.20 (m, 1H), 1.05 (br s, 1H); LCMS (M+H)=512.4; HPLC:RT=6.08 min (Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min; Flow:0.5 mL/min).

Example 892-{3-[4-(Methoxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-(4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Tetrabutylammonium fluoride (1M in THF, 16.1 mL, 16.1 mmol) was added toa room-temperature solution of (5)-methyl3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate,prepared in Example 88, Step 4 (750 mg, 1.07 mmol) in THF (10 mL). Theresulting mixture was stirred for 15 min. The reaction was quenched withsat. aq. NH₄Cl solution, transferred to a separatory funnel, andextracted with ethyl acetate. The extracts were combined, washed withsat. aq. NH₄Cl solution, water and brine, dried over anhydrous sodiumsulfate, filtered, and concentrated to provide a clear-yellow oil. Thecrude product was purified using ISCO silica gel chromatography (40 gcolumn, 0% to 100% ethyl acetate/dichloromethane) to give (S)-methyl3-(4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(500 mg, 0.977 mmol, 91%). Analytical Chiral SFC indicated 93% chiralpurity. The compound was submitted to preparative chiral SFC separationto give (S)-methyl3-(4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(400 mg, 0.782 mmol, 73% yield, >99.% chiral purity as determined byanalytical chiral SFC. LCMS (M+H)=512.3.

Step 2: (S)-Methyl3-(4-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Sodium hydride (60% in oil, 8.44 mg, 0.211 mmol) was added to a vialcontaining a 0° C. solution of (S)-methyl3-(4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(54.0 mg, 0.106 mmol) in DMF (1 mL). Gas evolution occurred and thereaction was stirred for 10 min before adding iodomethane (0.0130 mL,0.211 mmol). After 10 min, more sodium hydride (60% in oil, 8.44 mg,0.211 mmol) and iodomethane (0.0130 mL, 0.211 mmol) were added. Thereaction was quenched with sat. aq. NH₄Cl, diluted with ethyl acetate,transferred to a separatory funnel, washed with 10% LiCl solution, waterand brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to provide crude (S)-methyl3-(4-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(72.0 mg, 0.137 mmol, 130%) as a yellow oil. LCMS (M+H)=525.0. Theproduct was used without further purification.

Step 3:(S)-2-(3-(4-(Methoxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Methylmagnesium bromide (3M in Et₂O, 0.533 mL, 1.60 mmol) was added to a0° C. solution of (S)-methyl3-(4-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(56.0 mg, 0.107 mmol) in THF (1 mL). After 15 min, the reaction wasquenched cautiously with sat. aq. ammonium chloride solution,transferred to a separatory funnel, diluted with ethyl acetate, washedwith water and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to provide a clear oil. The oil was dissolved in a minimumof dichloromethane and purified on an ISCO companion chromatographysystem (12 g silica cartridge, eluting with 0-10%methanol/dichloromethane, 30 mL/min) to provide impure(S)-2-(3-(4-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(41.4 mg, 0.0790 mmol, 74%). LCMS (M+H)=526.4. HPLC: RT=3.02 min(Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A: 10:90methanol:water with 0.1% TFA; Mobile Phase B: 90:10 methanol:water with0.1% TFA; Gradient 0-100% B over 5 min; Flow: 1.0 mL/min). The productwas further purified by preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 17-57% Bover 25 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to provide(S)-2-(3-(4-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(32.4 mg, 0.0620 mmol, 58%), and its estimated purity by LCMS analysiswas 100%. Two analytical LC/MS injections were used to determine thefinal purity. HPLC (Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min,then a 0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at220.) RT: 1.59 min. LCMS (M+H)=526.3 nm. HPLC (Column: Waters AcquityUPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min; Detection: UV at 220 nm); HPLC RT: 1.39. LCMS (M+H)=526.3.¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.49 (br. s., 1H), 8.16 (m2H), 7.66 (d, J=7.4 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.38-7.30 (m, 2H),7.29-7.20 (m, 1H), 5.80 (d, J=11.1 Hz, 1H), 4.47 (s, 2H), 4.07 (br. s.,3H), 3.91 (d, J=6.1 Hz, 1H), 3.75 (d, J=9.1 Hz, 1H), 3.32-3.21 (m, 4H),2.51 (br. s., 2H), 1.70 (d, J=12.5 Hz, 1H), 1.59 (m 7H), 1.40-1.25 (m,1H), 1.11-0.93 (m, 1H).

Examples 90 & 912-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: N-Methoxy-N-methyloxane-4-carboxamide

In a 1 L RB flask, a solution of tetrahydro-2H-pyran-4-carboxylic acid(46.0 g, 353 mmol) in dichloromethane (250 mL) was treated with1,1′-carbonyldiimidazole (63.0 g, 389 mmol) portion-wise—cautionbubbling. After the addition was complete the mixture was stirred atroom temperature for 2 h and then treated portion wise withN,O-dimethylhydroxylamine, HCl (37.9 g, 389 mmol) and then stirredovernight at room temperature. Washed with water and brine, dried overMgSO₄, filtered, and concentrated to giveN-methoxy-N-methyloxane-4-carboxamide (55.0 g, 302 mmol, 85%) as lightamber oil. ¹H NMR (400 MHz, CDCl₃) δ 4.02 (ddd, J=11.4, 4.2, 2.1 Hz,2H), 3.71 (s, 3H), 3.46 (td, J=11.8, 2.2 Hz, 2H), 3.19 (s, 3H),1.93-1.80 (m, 2H), 1.69-1.62 (m, 2H).

Step 2: 4-Benzoyloxane

A solution of N-methoxy-N-methyloxane-4-carboxamide (5.00 g, 28.9 mmol)in Tetrahydrofuran (50 mL) in a RB flask was cooled to −78° C. in adry-ice/acetone bath under nitrogen. The solution was treated viasyringe with phenyllithium 1.8 M in dibutylether (24.1 mL, 43.3 mmol)slowly over 10 min. The resulting dark mixture was stirred in the bathfor 2 h before it was poured into ice/sat. aq. ammonium chloride andextracted into ethyl acetate. The organics were washed with water andbrine and concentrated. The light yellow oil was purified by silica gelcolumn chromatography on an ISCO Companion (120 g silica gel column) andeluted with an EtOAc/hexane gradient (10-50%). The fractions containingproduct were collected, and the volatiles were removed to give4-benzoyloxane (4.30 g, 22.6 mmol, 78%) as an almost colorless oil.LCMS: Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad)2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA. RT=0.78 min; (ES): m/z (M+H)⁺=191.1. HPLC:Chromolith ODS S5 4.6×50 mm (4 min grad) 0-100% B. Flow Rate=4 mL/min.Inj. Vol.=10 uL. Wavelength=220. Oven Temp.=40° C. Solvent A: 10%MeOH−90% H₂O−0.1% TFA. Solvent B: 90% MeOH−10% H₂O−0.1% TFA. HPLC:RT=1.65 min.

Step 3: Oxan-4-yl(phenyl)(²H)methanol

A solution of 4-benzoyloxane (300 mg, 1.58 mmol) in methanol (3 mL) in ascintillation vial was treated slowly portion-wise with sodiumborodeuteride 98% D (99.0 mg, 2.37 mmol)—immediate bubbling occurs.After the addition was complete, the mixture was stirred at roomtemperature for 1 h. The mixture was diluted with water and extractedinto ethyl acetate. The organics were washed with water and brine andconcentrated to give oxan-4-yl(phenyl)(²H)methanol (300 mg, 98%) as athick oil. This was used without further purification. HPLC: ChromolithODS S5 4.6×50 mm (4 min grad) 0-100% B. Flow Rate=4 mL/min. Inj. Vol.=10uL. Wavelength=220. Oven Temp.=40° C. Solvent A: 10% MeOH−90% H₂O−0.1%TFA. Solvent B: 90% MeOH −10% H₂O−0.1% TFA. HPLC: RT=1.443 min; LCMS:Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98%B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA. LCMS: RT=0.77 min; (ES): m/z (M+H-H₂O)⁺=176.1.

Step 4: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)(²H)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A suspension of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(249 mg, 0.776 mmol), phenyl(tetrahydro-2H-pyran-4-yl)(²H)methanol (300mg, 1.55 mmol), and triphenylphosphine (407 mg, 1.55 mmol) indichloromethane (5 mL) was stirred in a RB flask and treated drop wisewith DIAD (0.302 mL, 1.55 mmol). The mixture was stirred at roomtemperature for 16 h. The reaction mixture was added directly onto asilica gel column and was purified using silica gel columnchromatography with an ISCO Companion (40 g silica gel column) andeluted with ethyl acetate. The fractions containing product werecollected, and the volatiles were removed to give methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)(²H)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(190 mg, 0.383 mmol, 49%) as a white solid. LCMS: Waters Acquity SDS.Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8mL/min. Solvent A: H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1% TFA. LCMS:RT=0.89 min; (ES): m/z (M+H)⁺=497.2.

Step 5:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

In a RB flask, a solution of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)(²H)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(190 mg, 0.383 mmol) in tetrahydrofuran (10 mL) was cooled in an icebath under nitrogen and treated with methylmagnesium bromide (3M inether, 3.06 mL, 9.20 mmol). After 2 h the reaction was quenched withsat. aq. ammonium chloride and extracted into ethyl acetate. Theorganics were washed with water, and the volatiles were concentrated togive 120 mg of a white solid. The material was purified using silica gelcolumn chromatography on an ISCO Companion (40 g silica gel column) andeluted with (90:9:1 CH₂Cl₂:MeOH: NH₄OH)/CH₂Cl₂ gradient (0-100%). Thefractions containing the product were collected, and the volatiles wereremoved to give 150 mg of the racemate, which was separated by chiralprep SFC (Column: Chiral OD-H 25×3 cm, 5 μm; Mobile Phase: 70/30CO₂/MeOH; Flow: 85 mL/min) to give2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olEnantiomer A (50.0 mg, 26%) and2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(R)-oxan-4-yl(phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olEnantiomer B (50.0 mg, 26%). Enantiomer A: 1H NMR (400 MHz, CDCl₃) δ8.42 (d, J=1.8 Hz, 1H), 8.35 (dd, J=8.3, 0.5 Hz, 1H), 7.97 (d, J=0.7 Hz,1H), 7.55 (d, J=1.7 Hz, 1H), 7.48-7.40 (m, 3H), 7.37-7.27 (m, 3H), 4.05(dd, J=11.2, 3.3 Hz, 1H), 3.89-3.81 (m, 4H), 3.54 (td, J=11.9, 2.0 Hz,1H), 3.34 (td, J=11.9, 2.1 Hz, 1H), 3.13-3.03 (m, 1H), 2.29 (s, 3H),2.06-1.97 (m, 2H), 1.74 (s, 6H), 1.69-1.60 (m, 1H), 1.48-1.35 (m, 1H),1.11 (d, J=12.2 Hz, 1H). LCMS: RT=0.76 min; (ES): m/z (M+H)⁺=497.3(Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad)2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA). HPLC: RT=8.148 min; (Column: Sunfire C18 3.5 μm,3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100%B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220 nm). Chiral SFCRT=1.06 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:50/50 CO₂/(1:1 MeOH/CH₃CN); Flow: 2 mL/min). Enantiomer B: Chiral SFCRT=2.83 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:50/50 CO₂/MeOH Flow: 2 mL/min).

Examples 92 & 932-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(2-fluorophenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 4-(2-Fluorobenzoyl)oxane

A solution of 1-bromo-2-fluorobenzene (10.1 g, 57.7 mmol) intetrahydrofuran (50 mL) in a RB flask was cooled to −78° C. in a dry iceand acetone bath and treated slowly via syringe with nBuLi, 2.5 M inhexanes (23.1 mL, 57.7 mmol), and the resulting amber solution stirredfor 35 min in bath. The mixture was treated with a solutionN-methoxy-N-methyloxane-4-carboxamide (5.00 g, 28.9 mmol) in 10 mL oftetrahydrofuran via syringe to give a dark solution. After 2 h, themixture was quenched with sat. aq. NH₄Cl and extracted into ethylacetate. The organics were washed with water and brine, and thevolatiles were concentrated to give a dark-yellow oil. The materialpurified using silica gel column chromatography on an ISCO Companion(120 g silica gel column) and eluted with an EtOAc/hexane hexanegradient (10-40%). The fractions containing product were collected, andthe volatiles were removed were collected, and the volatiles wereremoved to give 4-(2-fluorobenzoyl)oxane (4.50 g, 21.6 mmol, 75%) as alight-amber oil. LCMS: Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA.Solvent B: Acetonitrile−0.1% TFA. LCMS: RT=0.81 min; (ES): m/z(M+H)⁺=209.1. HPLC: Chromolith ODS S5 4.6×50 mm (4 min grad) 0-100% B.Flow Rate=4 mL/min. Inj. Vol.=10 uL. Wavelength=220. Oven Temp.=40° C.Solvent A: 10% MeOH−90% H₂O−0.1% TFA. Solvent B: 90% MeOH−10% H₂O−0.1%TFA. HPLC: RT=1.797 min.

Step 2: 2-Fluorophenyl(oxan-4-yl)(²H)methanol

A solution of (2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanone (300mg, 1.44 mmol) in methanol (3 mL) in a scintillation vial was treatedslowly portion-wise with sodium borodeuteride (90.0 mg, 2.16mmol)—immediate bubbling occurs. After addition was complete, themixture was stirred at room temperature 1.5 h. The mixture was dilutedwith water and extracted into ethyl acetate. The organics were washedwith water and brine, and the volatiles were concentrated to give2-fluorophenyl(oxan-4-yl)(²H)methanol (304 mg, 100%) as a colorless oil.HPLC: Chromolith ODS S5 4.6×50 mm (4 min grad) 0-100% B. Flow Rate=4mL/min. Inj. Vol.=10 uL. Wavelength=220. Oven Temp.=40° C. Solvent A:10% MeOH−90% H₂O−0.1% TFA. Solvent B: 90% MeOH−10% H₂O−0.1% TFA. HPLC:RT=1.557 min.

Step 3:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(2-fluorophenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(R)-oxan-4-yl(2-fluorophenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(228 mg, 0.710 mmol) and(2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)(²H)methanol (300 mg, 1.42mmol) were converted to 150 mg of racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(2-fluorophenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC (Column: Chiral OD-H 25×3 cm, 5μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 85 mL/min) to give2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(2-fluorophenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olEnantiomer A (70.0 mg, 35%) and2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(R)-oxan-4-yl(2-fluorophenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olEnantiomer B (50.0 mg, 25%). Enantiomer A: 1H NMR (400 MHz, CDCl₃) δ8.46 (d, J=1.7 Hz, 1H), 8.36-8.30 (m, 1H), 8.01 (s, 1H), 7.82-7.72 (m,2H), 7.45 (dd, J=8.3, 1.4 Hz, 1H), 7.37-7.28 (m, 1H), 7.25-7.18 (m, 1H),7.04 (ddd, J=10.5, 8.2, 1.2 Hz, 1H), 4.05 (dd, J=10.6, 3.4 Hz, 1H), 4.00(s, 3H), 3.87 (dd, J=11.7, 2.4 Hz, 1H), 3.57-3.48 (m, 1H), 3.33 (td,J=11.9, 2.0 Hz, 1H), 3.16 (t, J=11.3 Hz, 1H), 2.37 (s, 3H), 1.95 (s,1H), 1.88 (d, J=12.3 Hz, 1H), 1.73 (d, J=2.9 Hz, 6H), 1.63 (m, 1H),1.47-1.34 (m, 1H), 1.12 (d, J=12.6 Hz, 1H). LCMS: RT=0.78 min; (ES): m/z(M+H)⁺=515.3 (Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA.Solvent B: Acetonitrile−0.1% TFA). HPLC: RT=8.133 min (Column: SunfireC18 3.5 μm, 3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 0-100% B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220nm). Chiral SFC RT=4.335 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: Chiral SFCRT=7.569 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:70/30 CO₂/MeOH; Flow: 2 mL/min).

Examples 94 & 952-{5-[(2,3-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: 4-(2,3-Difluorobenzoyl)oxane

A solution of 4-bromo-1,2-difluorobenzene (2.40 g, 12.4 mmol) intetrahydrofuran (20 mL) in a RB flask was cooled to −78° C. in a dry iceand acetone bath and treated slowly drop wise via syringe with nBuLi,2.5 M in hexanes (4.97 mL, 12.4 mmol) and stirred for 20 min in bath.The mixture was then treated with a solution ofN-methoxy-N-methyloxane-4-carboxamide (0.718 g, 4.15 mmol) in 2 mL oftetrahydrofuran via syringe to give a light-brown solution. After 1 h,the mixture was quenched with sat. aq. NH₄Cl and extracted into ethylacetate. The organics were washed with water and brine, and thevolatiles were concentrated to give an oil. Analysis by LCMS shows 2isomeric products formed. The material was purified by silica gel columnchromatography on an ISCO Companion (40 g silica gel column) and elutedwith an EtOAc/hexane hexane gradient (0-50%). The fractions containingthe major isomer were collected, and the volatiles were removed to give4-(2,3-difluorobenzoyl)oxane (350 mg, 37%) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 7.54 (ddt, J=7.9, 6.1, 1.7 Hz, 1H), 7.37 (dtd, J=9.5,8.0, 1.7 Hz, 1H), 7.20 (tdd, J=8.1, 4.6, 1.4 Hz, 1H), 4.05 (dt, J=11.4,3.5 Hz, 2H), 3.55 (td, J=11.3, 2.9 Hz, 2H), 3.42-3.30 (m, 1H), 1.93-1.74(m, 4H). The fractions containing the minor isomer were collected, andthe volatiles were removed to give 4-(3,4-difluorobenzoyl)oxane (130 mg,14%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.70 (m, 2H),7.33-7.22 (m, 1H), 4.11-4.01 (m, 2H), 3.56 (td, J=11.6, 2.5 Hz, 2H),3.43 (tt, J=11.0, 4.0 Hz, 1H), 1.95-1.82 (m, 2H), 1.81-1.71 (m, 2H).

Step 2: (2,3-Difluorophenyl)(oxan-4-yl)methanol

A solution of 4-(2,3-difluorobenzoyl)oxane (350 mg, 1.55 mmol) inmethanol (10 mL) was treated slowly portion wise with NaBH4 (88.0 mg,2.32 mmol)—immediate bubbling. After addition was complete, the mixturewas stirred at room temperature. The volatiles were removed, and theresidue was partitioned between sat. aq. NH₄Cl and ethyl acetate. Theorganics were washed with water, and the volatiles were concentrated togive (2,3-difluorophenyl)(oxan4-yl)methanol (350 mg, 99%) as a colorlessoil. LCMS: Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 mingrad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA. LCMS: RT=0.74 min; (ES): m/z (M+H-H₂O)⁺=211. ¹HNMR (400 MHz, CDCl₃) δ 7.26-7.17 (m, 1H), 7.14-7.06 (m, 2H), 4.80 (dd,J=7.2, 4.3 Hz, 1H), 4.03 (dd, J=11.4, 3.8 Hz, 1H), 3.95 (dd, J=10.9, 4.1Hz, 1H), 3.42-3.26 (m, 2H), 2.12 (d, J=4.4 Hz, 1H), 1.97-1.89 (m, 1H),1.89-1.80 (m, 1H), 1.56-1.39 (m, 2H), 1.31-1.23 (m, 1H).

Step 3:2-{5-[(2,3-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(R)-oxan-4-yl(phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(150 mg, 0.467 mmol) and(2,3-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (213 mg, 0.934mmol) were converted to 140 mg of racemic2-{5-[(2,3-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-olas a white solid, which was separated by chiral prep SFC (Column: ChiralOD-H 25×3 cm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 85 mL/min) togive Enantiomer A (50 mg, 23%) and Enantiomer B (40 mg, 22%). EnantiomerA: ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=1.7 Hz, 1H), 8.36 (d, J=8.2 Hz,1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.58-7.51 (m, 1H), 7.46 (dd, J=8.3, 1.3Hz, 1H), 7.23-7.11 (m, 2H), 5.77 (d, J=11.6 Hz, 1H), 4.12-4.05 (m, 1H),4.03 (s, 3H), 3.88 (dd, J=11.9, 2.6 Hz, 1H), 3.59-3.47 (m, 1H), 3.34(td, J=11.9, 2.1 Hz, 1H), 3.24-3.11 (m, 1H), 2.39 (s, 3H), 2.00 (s, 1H),1.88 (d, J=12.7 Hz, 1H), 1.74 (d, J=4.9 Hz, 6H), 1.67-1.53 (m, 1H),1.49-1.33 (m, 1H), 1.14 (d, J=11.7 Hz, 1H). LCMS: RT=0.78 min; (ES): m/z(M+H)⁺=532.4 (Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B.Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA). HPLC RT=9.133 min (Column: Sunfire C18 3.5 μm,3.0×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 0-100%B over 15 min; Flow: 0.5 mL/min; Detection: UV at 220 nm). Chiral SFCRT=6.660 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:75/25 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: Chiral SFC RT=11.635 min(Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH;Flow: 2 mL/min).

Examples 96 & 972-{5-[(3,4-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: 4-(3,4-Difluorobenzoyl)oxane

To a solution of 4-bromo-1,2-difluorobenzene (1.18 mL, 10.4 mmol) in dryTHF (50 mL) was added isopropylmagnesium chloride (5.21 mL, 10.4 mmol)via syringe and then stirred at room temperature for 2 h. A etheralsolution of N-methoxy-N-methyloxane-4-carboxamide (1.64 g, 9.47 mmol)was added, and the reaction mixture was stirred at room temperature for16 h. The reaction mixture was quenched with water (20 mL) and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated. The crude residue was also purified(24 g combiflash column/compound absorbed on silica, eluted at 10-5% EAin petroleum ether) to obtain 4-(3,4-difluorobenzoyl)oxane (700 mg, 32%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.70 (m, 2H),7.33-7.22 (m, 1H), 4.11-4.01 (m, 2H), 3.56 (td, J=11.6, 2.5 Hz, 2H),3.43 (tt, J=11.0, 4.0 Hz, 1H), 1.95-1.82 (m, 2H), 1.81-1.71 (m, 2H).

Step 2: (3,4-Difluorophenyl)(oxan-4-yl)methanol

To a stirred solution of 4-(3,4-difluorobenzoyl)oxane (2.80 g, 12.4mmol) in MeOH (60 mL) was added NaBH₄ (0.937 g, 24.8 mmol) portion wiseover the period of 2 min and then stirred at room temperature for 2 h.Methanol was evaporated, and the residue was quenched with ice water (55mL) and extracted with EtOAc(2×100 mL). The EtOAc extract was dried overNa₂SO₄, filtered, and concentrated to give(3,4-difluorophenyl)(oxan-4-yl)methanol (2.50 g, 11.0 mmol, 88%) as acolorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.10 (m, 2H), 7.03(ddd, J=1.8, 4.1, 8.2 Hz, 1H), 4.38 (dd, J=2.8, 7.3 Hz, 1H), 4.08-3.88(m, 2H), 3.42-3.23 (m, 2H), 1.97 (s, 1H), 1.91-1.72 (m, 2H), 1.50-1.29(m, 2H), 1.24-1.13 (m, 1H).

Step 3:2-{5-[(3,4-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,3-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(3,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (355 mg, 1.56mmol) was converted to 114 mg of racemic2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-olas a white solid which was separated by chiral prep HPLC (Column: LuxCellulose 4 25×2.1 cm, 5 μm; Mobile Phase: 70/30 0.2% DEA inhexane/methanol; Flow: 18 mL/min) to give Enantiomer A (20.0 mg, 8%) andEnantiomer B (40 mg, 16%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.47(d, J=2.0 Hz, 1H), 8.31 (d, J=8.0 Hz, 2H), 8.08 (s, 1H), 7.63 (ddd,J=2.3, 7.8, 11.5 Hz, 1H), 7.53-7.49 (m, 1H), 7.47-7.41 (m, 1H), 7.24(td, J=8.5, 10.5 Hz, 1H), 5.75 (d, J=11.0 Hz, 1H), 4.04 (s, 3H), 4.00(dd, J=2.8, 11.8 Hz, 1H), 3.82 (dd, J=2.8, 11.8 Hz, 1H), 3.60 (dt,J=2.0, 11.8 Hz, 1H), 3.45-3.34 (m, 2H), 2.34 (s, 3H), 1.89 (d, J=12.5Hz, 1H), 1.68 (d, J=4.0 Hz, 7H), 1.65-1.57 (m, 1H), 1.44-1.38 (m, 1H),1.13 (d, J=12.0 Hz, 1H). LCMS: RT=1.852 min; MS (ES): m/z=532.5 [M+H]⁺(ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm); HPLC RT=13.127 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 30 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral HPLC RT=15.105 min (Column: Lux Cellulose 4, 250×4.6 mm, 5μm; Mobile Phase: 70/30 0.2% DEA in Hexane/Methanol; Flow: 1 mL/min).Enantiomer B: Chiral HPLC RT=18.032 min (Column: Lux Cellulose 4,250×4.6 mm, 5 μm; Mobile Phase: 70/30 0.2% DEA in Hexane/Methanol; Flow:1 mL/min).

Examples 98 & 992-{5-[(3,5-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(3,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted to40 mg of racemic2-{5-[(3,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-olas a white solid which was separated by chiral prep SFC (Column: LuxCellulose-4, 25×2.1 cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inmethanol); Flow: 60 mL/min) to give Enantiomer A (14.0 mg, 8%) andEnantiomer B (14.0 mg, 8%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.47(d, J=1.5 Hz, 1H), 8.30 (d, J=8.0 Hz, 2H), 8.08 (s, 1H), 7.51 (dd,J=1.3, 8.3 Hz, 1H), 7.36-7.23 (m, 2H), 6.93-6.84 (m, 1H), 5.76 (d,J=11.0 Hz, 1H), 4.08-3.94 (m, 4H), 3.86-3.77 (m, 1H), 3.64-3.54 (m, 1H),3.44-3.33 (m, 2H), 2.33 (s, 3H), 1.92-1.83 (m, 1H), 1.73-1.57 (m, 7H),1.45-1.36 (m, 1H), 1.14 (d, J=13.6 Hz, 1H). LCMS: RT=2.423 min; MS (ES):m/z=532.2, [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm(50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=8.633 min(Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=3.58 min (Column: LuxCellulose 4, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inmethanol; Flow: 4 mL/min). Enantiomer B: Chiral SFC RT=4.69 min (Column:Lux Cellulose 4, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inmethanol; Flow: 4 mL/min).

Examples 100 & 1012-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(3-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(3-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (355 mg, 1.56 mmol)was converted to 120 mg of racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(3-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olas a white solid, which was separated by chiral prep SFC (Column: ChiralOD-H 25×2.1 cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow:70 mL/min) to give Enantiomer A (48.0 mg, 19%) and Enantiomer B (47.0mg, 18%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J=1.5 Hz,1H), 8.32-8.27 (m, 2H), 8.11 (s, 1H), 7.53-7.48 (m, 1H), 7.46-7.40 (m,2H), 7.39-7.32 (m, 1H), 7.06-6.98 (m, 1H), 5.78 (d, J=11.5 Hz, 1H), 4.02(s, 3H), 3.98 (d, J=3.0 Hz, 1H), 3.82 (dd, J=2.5, 11.5 Hz, 1H), 3.60(dt, J=2.3, 11.9 Hz, 1H), 3.43-3.33 (m, 2H), 2.33 (s, 3H), 1.92 (d,J=13.1 Hz, 1H), 1.71-1.66 (m, 7H), 1.48-1.33 (m, 1H), 1.13 (d, J=12.0Hz, 1H). LCMS: RT=1.822 min; MS (ES): m/z=514 [M+H]⁺ (ACN/H₂O withHCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm, gradient=4 min,wavelength=220 nm); HPLC RT=8.155 min (Column: Sunfire C18 3.5 μm,4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 10-100%B over 15 min; Flow: 1 mL/min; Detection: UV at 220 nm). Chiral SFCRT=6.16 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:70/30 CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFCRT=3.81 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:70/30 CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min).

Examples 102 & 1032-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,4,6-trifluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was convertedto 40 mg of racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olas a white solid, which was separated by chiral prep SFC (Column:Chiralpak OJ-H 25×2.1 cm, 5 μm; Mobile Phase: 80/20 CO₂/(0.25% DEA inMeOH); Flow: 60 mL/min) to give Enantiomer A (12.0 mg, 6%) andEnantiomer B (11.0 mg, 6%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.50(d, J=2.0 Hz, 1H), 8.37 (br. s., 1H), 8.33-8.27 (m, 1H), 8.10-8.03 (m,1H), 7.52 (dd, J=1.5, 8.5 Hz, 1H), 7.02-6.92 (m, 2H), 6.04 (d, J=12.0Hz, 1H), 4.15-4.07 (m, 3H), 4.06-3.98 (m, 1H), 3.80 (d, J=11.5 Hz, 1H),3.60-3.51 (m, 1H), 3.46-3.34 (m, 2H), 2.42-2.37 (m, 3H), 1.79 (d, J=11.5Hz, 1H), 1.71-1.55 (m, 7H), 1.40 (d, J=8.0 Hz, 1H), 1.09 (br. s., 1H).LCMS: RT=2.394 min; MS (ES): m/z=550.2 [M+H]⁺ (ACN/H₂O with HCOONH₄,Ascentis Express C18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220nm); HPLC RT=8.445 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; MobilePhase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=2.94 min (Column:Chiralpak OJ-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=4.29 min (Column:Chiralpak OJ-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 104 & 1052-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,4,6-trifluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC (Column: Lux Cellulose-2, 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 60 mL/min)to give Enantiomer A (17.0 mg, 33%) and Enantiomer B (19.0 mg, 37%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.53 (d, J=1.5 Hz, 1H), 8.43(br. s., 1H), 7.85 (s, 1H), 7.27-7.21 (m, 1H), 7.04-6.95 (m, 2H), 6.07(d, J=11.5 Hz, 1H), 4.11 (s, 3H), 4.03 (d, J=14.6 Hz, 1H), 3.85-3.77 (m,1H), 3.59-3.51 (m, 1H), 3.43-3.35 (m, 2H), 2.40 (s, 3H), 1.78 (d, J=11.5Hz, 1H), 1.69-1.61 (m, 7H), 1.42 (m, 1H), 1.07 (d, J=11.5 Hz, 1H). LCMS:RT=1.859 min; MS (ES): m/z=568.2 [M+H]⁺ (ACN/H₂O with HCOONH₄, AscentisExpress C18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLCRT=9.155 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=8.15 min (Column: LuxCellulose-2, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=9.58 min (Column:Lux Cellulose-2, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 106 & 1072-{5-[(2,5-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,5-difluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to racemic2-{5-[(2,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC (Column: Chiralcel OD-H, 25×2.1cm, 5 μm; Mobile Phase: 80/20 CO₂/(0.25% DEA in MeOH); Flow: 60 mL/min)to give Enantiomer A (22.0 mg, 44%) and Enantiomer B (25.0 mg, 48%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.49 (d, J=2.0 Hz, 1H), 8.39(br. s., 1H), 7.99-7.90 (m, 1H), 7.83 (br. s., 1H), 7.21 (d, J=12.5 Hz,1H), 7.14-7.04 (m, 2H), 5.99 (d, J=11.5 Hz, 1H), 4.05 (s, 3H), 4.02-3.95(m, 1H), 3.81 (dd, J=2.8, 11.8 Hz, 1H), 3.65-3.56 (m, 1H), 3.42-3.34 (m,2H), 2.35 (s, 3H), 1.97-1.86 (m, 1H), 1.72-1.59 (m, 7H), 1.45-1.40 (m,1H), 0.98 (d, J=13.1 Hz, 1H). LCMS: RT=1.85 min; MS (ES): m/z=550.2[M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm); HPLC RT=8.838 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=8.39 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm;Mobile Phase: 75/25 CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min). EnantiomerB: Chiral SFC RT=10.10 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm;Mobile Phase: 75/25 CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min).

Examples 108 & 1092-{5-[(2,3-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,3-difluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to racemic2-{5-[(2,3-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC (Column: Chiralcel OD-H, 25×2.1cm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA in MeOH); Flow: 75 mL/min)to give Enantiomer A (22.0 mg, 44%) and Enantiomer B (15.0 mg, 30%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.52 (d, J=1.5 Hz, 1H), 8.39(br. s., 1H), 7.97-7.82 (m, 2H), 7.39-7.19 (m, 3H), 6.07 (d, J=11.5 Hz,1H), 4.12-3.99 (m, 4H), 3.83 (dd, J=3.0, 11.5 Hz, 1H), 3.67-3.56 (m,1H), 3.46-3.37 (m, 2H), 2.37 (s, 3H), 1.93 (d, J=13.6 Hz, 1H), 1.76-1.61(m, 7H), 1.49-1.40 (m, 1H), 0.99 (d, J=12.5 Hz, 1H). LCMS: RT=1.85 min;MS (ES): m/z=550.2 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C182.7 μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=8.918min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=2.609 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT 4.36 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 110 & 1112-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,4-difluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to racemic2-{5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC (Column: Chiralpak IC, 25×2.1 cm,5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 60 mL/min) togive Enantiomer A (12.0 mg, 21%) and Enantiomer B (10.0 mg, 17%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J=1.5 Hz, 1H), 8.37(br. s., 1H), 8.19-8.10 (m, 1H), 7.80 (br. s., 1H), 7.24-7.07 (m, 2H),6.95 (ddd, J=2.5, 8.7, 10.9 Hz, 1H), 5.97 (d, J=11.5 Hz, 1H), 4.09-3.97(m, 4H), 3.81 (d, J=9.0 Hz, 1H), 3.64-3.55 (m, 1H), 3.42-3.35 (m, 2H),2.36 (s, 3H), 1.90 (t, J=5.8 Hz, 2H), 1.70-1.60 (m, 7H), 1.45-1.39 (m,1H), 0.96 (d, J=14.6 Hz, 1H). LCMS: RT=1.86 min; MS (ES): m/z=550.2[M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm); HPLC RT=9.112 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=10.61 min (Column: Chiralpak IC, 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). EnantiomerB: Chiral SFC RT=12.94 min (Column: Chiralpak IC, 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Examples 112 & 1132-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(3-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(3-fluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(3-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC (Column: Chiralcel OD-H, 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 75 mL/min)to give Enantiomer A (5.00 mg, 9%) and Enantiomer B (15.0 mg, 29%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.40 (d, J=2.0 Hz, 1H), 8.2 (br.s., 1H), 7.81 (s, 1H), 7.34-7.26 (m, 3H), 7.18 (m, 1H), 6.91 (m, 1H),5.70 (d, J=11.5 Hz, 1H), 3.92 (s, 3H), 3.90 (d, J=3.0 Hz, 1H), 3.72 (d,J=3.0 Hz, 1H), 3.51 (m, 1H), 3.40-3.37 (m, 2H), 2.23 (s, 3H), 1.93 (d,J=13.6 Hz, 1H), 1.76-1.61 (m, 7H), 1.49-1.40 (m, 1H), 0.99 (d, J=12.5Hz, 1H). LCMS: RT=1.85 min; MS (ES): m/z=532.2 [M+H]⁺ (ACN/H₂O withHCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm, gradient=4 min,wavelength=220 nm). HPLC RT=8.907 min (Column: Sunfire C18 3.5 μm,4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 10-100%B over 15 min; Flow: 1 mL/min; Detection: UV at 220 nm). Chiral SFCRT=2.09 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase:60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). Enantiomer B: Chiral SFCRT 3.00 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase:60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Example 1142-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(R)-(2-fluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.LCMS: RT=1.617 min; (ES): m/z (M+H)⁺=532.2; (Column: Waters Acquity UPLCBEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). ¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (br. s., 1H), 8.23 (br.s., 1H), 7.96 (s, 1H), 7.46-7.26 (m, 3H), 7.22 (d, J=11.4 Hz, 1H),7.18-7.05 (m, 1H), 6.05 (d, J=11.4 Hz, 1H), 4.01 (br. s., 3H), 3.94-3.86(m, 1H), 3.73 (d, J=9.4 Hz, 1H), 3.49 (br. s., 1H), 3.22 (t, J=11.4 Hz,1H), 2.30 (br. s., 3H), 1.75 (d, J=11.1 Hz, 1H), 1.69-1.60 (m, 2H), 1.55(br. s., 6H), 1.36 (d, J=9.1 Hz, 1H).

Examples 115 & 1165-{5-[(2-Fluorophenyl)(oxan-4-yl)methyl]-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2-fluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-methanesulfonyl-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to racemic5-{5-[(2-fluorophenyl)(oxan-4-yl)methyl]-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,which was separated by chiral prep SFC (Column: Chiralcel OD-H, 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 75 mL/min)to give Enantiomer A (14.0 mg, 9%) and Enantiomer B (15.0 mg, 9%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.71 (d, J=2.0 Hz, 1H), 8.42(br. s., 2H), 8.21-8.14 (m, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.84 (br. s.,1H), 7.43-7.33 (m, 2H), 7.12-7.03 (m, 1H), 6.16 (d, J=11.5 Hz, 1H),4.10-3.98 (m, 4H), 3.85-3.77 (m, 4H), 3.63 (dd, J=10.0, 11.5 Hz, 1H),3.49-3.36 (m, 2H), 2.37 (s, 3H), 2.03-1.94 (m, 1H), 1.76-1.62 (m, 1H),1.45 (dt, J=7.8, 12.4 Hz, 1H), 0.92 (d, J=14.1 Hz, 1H). LCMS: RT=1.863min; MS (ES): m/z=534.2 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis ExpressC18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220 nm). HPLCRT=9.004 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=3.58 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 4 mL/min). Enantiomer B: Chiral SFC RT 6.18 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 4 mL/min).

Examples 117 & 1185-{9-Methanesulfonyl-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,4,6-trifluorophenyl)(oxan-4-yl)methanol and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-methanesulfonyl-5H-pyrido[3,2-b]indole-7-carboxylatewere converted to racemic5-{9-methanesulfonyl-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,which was separated by chiral prep SFC (Column: Chiralcel OD-H, 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 75 mL/min)to give Enantiomer A (13.0 mg, 8%) and Enantiomer B (13.0 mg, 8%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.76 (d, J=1.5 Hz, 1H), 8.47(br. s., 1H), 8.34 (br. s., 1H), 8.11 (d, J=7.0 Hz, 1H), 7.93-7.82 (m,1H), 7.02 (t, J=9.0 Hz, 2H), 6.22 (d, J=11.5 Hz, 1H), 4.14 (s, 3H), 4.05(d, J=11.5 Hz, 1H), 3.86-3.76 (m, 4H), 3.61-3.52 (m, 1H), 3.46-3.36 (m,2H), 2.42 (s, 3H), 1.83 (d, J=12.0 Hz, 1H), 1.77-1.63 (m, 1H), 1.50-1.39(m, 1H), 1.01 (d, J=12.5 Hz, 1H). LCMS: RT=1.898 min; MS (ES): m/z=570.2[M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm). HPLC RT=9.683 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=3.18 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). EnantiomerB: Chiral SFC RT 4.78 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Examples 119 & 1202-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(2-fluoro-4-methoxyphenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2-fluoro-4-methoxyphenyl)(tetrahydro-2H-pyran-4-yl)methanol wasconverted to racemin2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(2-fluoro-4-methoxyphenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated using chiral prep SFC (Column: Chiral OD-H 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 70 mL/min)to give 2 enantiomers. Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d,J=1.5 Hz, 1H), 8.30 (d, J=8.0 Hz, 2H), 8.06 (s, 1H), 7.98 (t, J=8.8 Hz,1H), 7.53-7.47 (m, 1H), 6.89 (dd, J=2.0, 8.5 Hz, 1H), 6.68 (dd, J=2.5,12.5 Hz, 1H), 5.92 (d, J=11.5 Hz, 1H), 4.10-3.97 (m, 4H), 3.86-3.75 (m,4H), 3.66-3.57 (m, 1H), 3.43-3.36 (m, 2H), 2.42-2.34 (m, 3H), 1.95 (d,J=9.5 Hz, 1H), 1.72-1.60 (m, 7H), 1.43 (dq, J=4.5, 12.4 Hz, 1H), 0.98(d, J=12.0 Hz, 1H). LCMS: RT=1.831 min; MS (ES): m/z=544.4 [M+H]⁺(ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm); HPLC RT=8.114 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=2.20 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). EnantiomerB: Chiral SFC RT=3.40 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Examples 121 & 1222-{5-[(2,3-Difluoro-4-methoxyphenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,3-difluoro-4-methoxyphenyl)(tetrahydro-2H-pyran-4-yl)methanol wasconverted to racemic2-{5-[(2,3-difluoro-4-methoxyphenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated using chiral prep SFC (Column: Chiral OD-H 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 70 mL/min)to give 2 enantiomers. Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ ppm 8.46(d, J=1.51 Hz, 1H) 8.29 (d, J=8.53 Hz, 2H) 8.02 (s, 1H) 7.78 (t, J=7.28Hz, 1H) 7.48 (d, J=8.03 Hz, 1H) 7.03 (t, J=7.28 Hz, 1H) 5.92 (d, J=11.04Hz, 1H) 4.05 (s, 3H) 3.99 (d, J=9.04 Hz, 1H) 3.88 (s, 3H) 3.79 (d,J=10.04 Hz, 1H) 3.58 (t, J=11.04 Hz, 1H) 3.34-3.40 (m, 2H) 2.35 (s, 3H)1.91 (d, J=11.55 Hz, 1H) 1.57-1.70 (m, 7H) 1.37-1.46 (m, 1H) 0.95 (d,J=14.06 Hz, 1H). LCMS: RT=2.38 min; MS (ES): m/z=560 [M−H]— (ACN/H₂Owith HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm, gradient=4 min,wavelength=220 nm); HPLC RT=7.953 min (Column: Sunfire C18 3.5 μm,4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 10-100%B over 15 min; Flow: 1 mL/min; Detection: UV at 220 nm). Chiral SFCRT=2.19 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). Enantiomer B: Chiral SFCRT=3.27 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Examples 123 & 1242-{5-[(2,5-Difluoro-4-methoxyphenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,5-difluoro-4-methoxyphenyl)(tetrahydro-2H-pyran-4-yl)methanol wasconverted to racemic2-{5-[(2,5-difluoro-4-methoxyphenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated using chiral prep SFC (Column: Lux Cellulose −4,25×2.1 cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in methanol); Flow:75 mL/min) to give 2 enantiomers. Enantiomer A: ¹H NMR (400 MHz, CD₃OD)δ ppm 8.46 (d, J=1.51 Hz, 1H) 8.34 (br. s., 1H) 8.28 (d, J=8.03 Hz, 1H)8.03 (s, 1H) 7.89 (dd, J=12.05, 7.03 Hz, 1H) 7.49 (dd, J=8.28, 1.25 Hz,1H) 6.89 (dd, J=11.55, 7.03 Hz, 1H) 5.91 (d, J=11.55 Hz, 1H) 4.06 (s,3H) 4.00 (d, J=7.03 Hz, 1H) 3.76-3.84 (m, 4H) 3.60 (t, J=10.79 Hz, 1H)3.35-3.41 (m, 2H) 2.36 (s, 3H) 1.83-1.93 (m, 1H) 1.58-1.69 (m, 7H) 1.43(br. s., 1H) 0.99 (d, J=13.05 Hz, 1H). LCMS: RT=1.83 min; MS (ES):m/z=562 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm(50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=7.953 min(Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=6.70 min (Column: LuxCellulose −4, 250×21 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inmethanol); Flow: 4 mL/min). Enantiomer B: Chiral SFC RT=12.06 min(Column: Lux Cellulose −4, 250×21 mm, 5 μm; Mobile Phase: 60/40CO₂/(0.25% DEA in methanol); Flow: 4 mL/min).

Examples 125 & 1262-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate and(2,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol were converted toracemic2-{5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated using chrial prep SFC (Column: Chiral OD-H 25×2.1cm, 5 μm; Mobile Phase: 75/25 CO₂/(0.25% DEA in MeOH); Flow: 70 mL/min)to give 2 enantiomers. Enantiomer A: ¹H NMR (400 MHz, d4-MeOH) δ 8.39(m, 1H), 8.28-8.12 (m, 3H), 8.02 (m, 1H), 7.47 (d, J=9.6 Hz, 1H), 7.12(m, 1H), 6.96 (m, 1H), 5.95 (d, J=11.2 Hz, 1H), 4.03 (m, 1H), 3.81 (m,1H), 3.61 (m, 1H), 3.33 (m, 3H), 2.51 (s, 3H), 2.35 (s, 3H), 1.91 (m,1H), 1.68 (s, 6H), 1.64 (m, 1H), 1.43 (m, 1H), 0.99 (m, 1H). LCMS:RT=2.00 min; MS (ES): m/z=532.5 [M+H]⁺ (ACN/H₂O with HCOONH₄, AscentisExpress C18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLCRT=8.530 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=4.06 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=4.87 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 75/25 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 127 & 1282-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate and(2,4,6-trifluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol were convertedto racemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated using chiral prep SFC (Column: Lux Cellulose −2,25×2.1 cm, 5 μm; Mobile Phase: 75/25 CO₂/(0.25% DEA in methanol); Flow:60 mL/min) to give 2 enantiomers. Enantiomer A: ¹H NMR (400 MHz,d4-MeOH) δ 8.42 (m, 1H), 8.28 (m, 2H), 8.06 (m, 1H), 7.52 (m, 1H), 6.99(t, J=8.0 Hz, 2H), 6.05 (d, J=11.6 Hz, 1H), 4.04 (m, 1H), 3.83 (m, 1H),3.66 (m, 1H), 3.57 (m, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 1.81 (m, 1H),1.67 (m, 8H), 1.41 (m, 1H), 1.16 (m, 1H). LCMS: RT=2.01 min; MS (ES):m/z=550.5 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm(50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=8.529 min(Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=7.40 min (Column: LuxCellulose −2, 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/(0.25% DEA inmethanol); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=8.59 min(Column: Lux Cellulose −2, 250×4.6 mm, 5 μm; Mobile Phase: 70/30CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min).

Examples 129 & 1302-{5-[(3,5-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,methyl3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate and(3,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol were converted toracemic2-{5-[(3,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated using chiral prep SFC (Column: Lux Cellulose −2,25×2.1 cm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA in methanol); Flow:60 mL/min) to give 2 enantiomers. Enantiomer A: ¹H NMR (400 MHz, CD₃OD)δ 8.43-8.38 (m, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 8.09 (s, 1H),7.54-7.48 (m, 1H), 7.30 (d, J=6.5 Hz, 2H), 6.96-6.87 (m, 1H), 5.77 (d,J=11.0 Hz, 1H), 4.02 (d, J=12.0 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H),3.69-3.58 (m, 1H), 3.48-3.36 (m, 2H), 2.49 (s, 3H), 2.33 (s, 3H), 1.92(d, J=12.5 Hz, 1H), 1.70 (d, J=4.0 Hz, 6H), 1.67 (m, 1H), 1.43 (m, 1H),1.16 (d, J=12.5 Hz, 1H). LCMS: RT=2.26 min; MS (ES): m/z=532.2 [M+H]⁺(ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm); HPLC RT=8.948 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=3.79 min (Column: Lux Cellulose −2, 250×4.6 mm, 5 μm;Mobile Phase: 70/30 CO₂/(0.25% DEA in methanol); Flow: 3 mL/min).Enantiomer B: Chiral SFC RT=4.67 min (Column: Lux Cellulose −2, 250×4.6mm, 5 μm; Mobile Phase: 70/30 CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min).

Examples 131 & 1322-{5-[(2,5-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-bromo-5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (300mg, 0.983 mmol) and(2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (449 mg, 1.97mmol) in DCM (18 mL) was added triphenylphosphine (516 mg, 1.97 mmol)and DIAD (0.382 mL, 1.97 mmol) drop wise over the period of 2 min at 25°C., and the resulting mixture was stirred at room temperature for 16 h.The mixture was purified using silica gel column chromatography on anISCO Companion (24 g silica gel flash column) using a gradient of 0 to1% MeOH/CHCl₃ over 30 min. Fractions containing product were combinedand concentrated, and the solid obtained was triturated with diethylether (10 mL) to give methyl3-bromo-5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(200 mg, 37%) as a white solid. LCMS: HPLC: RT=1.21 min, MS (ES):m/z=515, 517 [M+H]⁺; (ACN/H₂O with NH₄OAc, Acquity BEH C18 1.7 μm(50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 2: Methyl5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A stirred solution of methyl3-bromo-5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(0.400 g, 0.287 mmol) and1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (0.122 g, 0.316 mmol)in DMF (1.5 ml) was purged under a stream of nitrogen for several min.To the mixture was added tetrakis(triphenylphosphine) palladium (0.022g, 0.0190 mmol), copper(I) iodide (8.20 mg, 0.0430 mmol), and Et₃N(0.0800 mL, 0.574 mmol), and the mixture was heated to 95° C. for 2 h ina microwave. The mixture was diluted with water (20 mL) and extractedwith EtOAc (30 mL×2), and the extracts concentrated. The residue waspurified using silica gel column chromatography (ISCO, Silica adsorbed,12 g flash column, 0 to 1.5% MeOH/CHCl₃ over 30 min). Fractionscontaining the product were concentrated to give methyl5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(0.100 g, 0.188 mmol, 66%) as a white solid. LCMS: HPLC: RT=1.04 min, MS(ES): m/z=532 [M+H]⁺; (ACN/H₂O with NH₄OAc, Acquity BEH C18 1.7 μm(50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 3:2-{5-[(2,5-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described in Step 2 for thesynthesis of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)(²H)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylatewas converted to racemic2-{5-[(2,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-olas a white solid, which was separated by chiral prep SFC (Column: ChiralOD-H 25×2.1 cm, 5 μm; Mobile Phase: 80/20 CO₂/(0.25% DEA in MeOH); Flow:70 mL/min) to give Enantiomer A (20.0 mg, 20%) and Enantiomer B (16.0mg, 16%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=2.0 Hz,1H), 8.37 (br. s., 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.98-7.88 (m, 1H),7.54-7.46 (m, 1H), 7.14-7.05 (m, 2H), 5.98 (d, J=11.0 Hz, 1H), 4.06 (s,3H), 4.00 (d, J=8.5 Hz, 1H), 3.81 (br. s., 1H), 3.66-3.57 (m, 1H),3.43-3.34 (m, 2H), 2.36 (s, 3H), 1.90 (d, J=13.1 Hz, 1H), 1.70-1.61 (m,7H), 1.43 (dt, J=7.8, 12.4 Hz, 1H), 1.00 (d, J=13.6 Hz, 1H). LCMS:RT=1.822 min; MS (ES): m/z=532.5 [M+H]⁺ (ACN/H₂O with HCOONH₄, AscentisExpress C18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLCRT=8.178 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=8.76 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=8.17 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 133 & 1342-{5-[(2,6-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,6-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted toracemic2-{5-[(2,6-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC (Column: Chiral OD-H 25×2.1 cm, 5μm; Mobile Phase: 70/30 CO₂/(0.25% DEA in MeOH); Flow: 60 mL/min) togive Enantiomer A (30.0 mg, 22%) and Enantiomer B (30.0 mg, 22%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD): δ 8.50-8.51 (m, 1H), 8.41 (s,1H), 8.32 (d, J=8.00 Hz, 1H), 7.54-7.56 (m, 1H), 7.40-7.44 (m, 1H),7.39-7.43 (m, 1H), 7.05-7.09 (m, 2H), 6.09-6.12 (m, 1H), 4.12 (s, 3H),4.03-4.06 (m, 1H), 3.81-3.84 (m, 1H), 3.54-3.62 (m, 1H), 3.45-3.51 (m,1H), 2.41 (s, 3H), 1.82-1.85 (m, 1H), 1.70 (s, 6H), 1.31-1.46 (m, 2H),1.23-1.31 (m, 1H), 1.08-1.12 (m, 1H). LCMS: RT=2.43 min; MS (ES):m/z=532.2 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm(50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=8.053 min(Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=7.83 min (Column: LuxCellulose 2, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 4 mL/min). Enantiomer B: Chiral SFC RT=9.03 min (Column:Lux Cellulose 2, 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 4 mL/min).

Examples 135 & 1362-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted toracemic2-{5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC (Column: Lux Cellulose 4,250×21.5 mm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA in MeOH); Flow: 70mL/min)) to give Enantiomer A (26.0 mg, 8%) and Enantiomer B (20.0 mg,6%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD): δ 8.46 (m, 1H), 8.32-8.27(m, 2H), 8.14 (m, 1H), 8.01 (m, 1H), 7.48 (dd, J=8.0, 0.8 Hz, 1H), 7.10(m, 1H), 6.93 (m, 1H), 5.95 (d, J 11.2 Hz, 1H), 4.05 (s, 3H), 3.99 (m,1H), 3.79 (m, 1H), 3.58 (m, 1H), 3.36 (m, 2H), 2.35 (s, 3H), 1.89 (m,1H), 1.66 (s, 3H), 1.64 (s, 3H), 1.61 (m, 1H), 1.41 (m, 1H), 0.95 (m,1H). LCMS: RT=1.84 min; MS (ES): m/z=532.2 [M+H]⁺ (ACN/H₂O with HCOONH₄,Ascentis Express C18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220nm); HPLC RT=8.301 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; MobilePhase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=4.32 min (Column: LuxCellulose 4, 250×4.6 mm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA inMeOH); Flow: 4 mL/min). Enantiomer B: Chiral SFC RT=9.15 min (Column:Lux Cellulose 4, 250×4.6 mm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA inMeOH); Flow: 4 mL/min).

Examples 137 & 1382-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(2-fluorophenyl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2-fluorophenyl)(oxan-4-yl)methanol and methyl3-bromo-9-methoxyl-5H-pyrido[3,2-b]indole-7-carboxylate were convertedto racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(2-fluorophenyl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,which was separated by chiral prep SFC (Column: Chiral OD-H 25×2.1 cm, 5μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 60 mL/min) togive Enantiomer A (30.0 mg, 22%) and Enantiomer B (30.0 mg, 22%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.4 (s, 1H), 8.3 (br. s., 1H),8.1 (td, J=7.5, 2.0 Hz, 1H), 7.6 (s, 1H), 7.3-7.4 (m, 2H), 7.0-7.1 (m,2H), 6.0 (d, J=11.5 Hz, 1H), 4.1 (s, 3H), 4.0-4.1 (m, 4H), 3.8 (dd,J=11.5, 3.0 Hz, 1H), 3.6-3.7 (m, 1H), 3.4 (d, J=12.0 Hz, 2H), 2.4 (s,3H), 1.9 (d, J=13.1 Hz, 1H), 1.6-1.7 (m, 7H), 1.4 (qd, J=12.3, 4.3 Hz,1H), 1.0 (d, J=13.1 Hz, 1H). LCMS: RT=1.76 min; MS (ES): m/z=544.4[M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm); HPLC RT=7.960 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=1.90 min (Column: Chiral OD-H 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). EnantiomerB: Chiral SFC RT=2.90 min (Column: Chiral OD-H 250×4.6 mm, 5 μm; MobilePhase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Examples 139 & 1402-{5-[(2,5-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-bromo-5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (300mg, 0.983 mmol) and(2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (449 mg, 1.97mmol) in DCM (18 mL) was added triphenylphosphine (516 mg, 1.97 mmol)and DIAD (0.382 mL, 1.97 mmol) drop wise over the period of 2 min at 25°C., and the resulting mixture stirred at room temperature for 16 h. Themixture was purified using silica gel column chromatography on an ISCOCompanion (24 g silica gel flash column, 0 to 1% MeOH/CHCl₃ over 30min). Fractions containing product were combined and concentrated, andthe solid obtained was triturated with diethyl ether (10 mL) to givemethyl3-bromo-5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(250 mg, 49%) as a white solid. LCMS: HPLC: RT=1.19 min, MS (ES):m/z=515, 517 [M+H]⁺; (ACN/H₂O with NH₄OAc, Acquity BEH C18 1.7 μm(50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 2: Methyl5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl3-bromo-5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(200 mg, 0.388 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(130 mg, 0.582 mmol), K₂CO₃ (161 mg, 1.16 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (31.7 mg, 0.0390 mmol), 1,4-dioxane (6.5 mL), and water (1.3 mL)in a vial was purged with a stream of argon for 5 min. The vial wascapped with a septum, evacuated and filled with argon, and then washeated to 100° C. for 1 h. The mixture was diluted with 30 mL of waterand extracted with EtOAc (45 mL×2), dried over Na₂SO₄, filtered,concentrated, and crude product was purified using silica gel columnchromatography using an ISCO (Silica gel, 12 g flash column, 0 to 2%MeOH/CHCl₃ over 30 min) to give methyl5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(200 mg, 0.376 mmol, 97%) as a yellow liquid. LCMS: RT=0.96 min; MS(ES): m/z=532 [M+1]⁺ (ACN/H₂O with NH₄OAc, Acquity BEH C18 1.7 μm(50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 3:2-{5-[(2,5-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

A stirred solution of methyl5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(150 mg, 0.282 mmol) in tetrahydrofuran (1 mL) was cooled to −20° C. andtreated with methylmagnesium bromide (3M in THF, 0.470 mL, 1.41 mmol)via syringe, and after addition was complete the reaction mixture wasslowly warmed to room temperature over a period of 5 h. The mixture wascooled in an ice bath, quenched with sat. aq. NH₄Cl (20 mL), and theaqueous layer was extracted with EtOAc (30 mL×2). The extract was driedover Na₂SO₄, filtered, concentrated, and the residue purified by prepHPLC (Column: Sunfire C18(250×30*7 u) Mobile Phase A: 10 mm NH₄OAc inwater, Mobile Phase B: ACN Solubility: MEOH+THF, Flow: 30 mL/min) togive racemic2-{5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl]-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(100 mg, 0.184 mmol, 65%) as a white solid, which was separated bychiral prep SFC (Column: Chiral OD-H 25×2.1 cm, 5 μm; Mobile Phase:85/15 CO₂/(0.25% DEA in MeOH); Flow: 60 mL/min) to give Enantiomer A (40mg, 26%) and Enantiomer B (40 mg, 26%). Enantiomer A: ¹H NMR (400 MHz,CD₃OD) δ 8.38 (d, J=1.8 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.20 (br. s.,1H), 8.02 (s, 1H), 7.93 (d, J=7.3 Hz, 1H), 7.47 (dd, J=1.3, 8.3 Hz, 1H),7.13-7.05 (m, 2H), 5.95 (d, J=11.5 Hz, 1H), 4.00 (dd, J=2.8, 11.5 Hz,1H), 3.80 (dd, J=3.0, 11.8 Hz, 1H), 3.67-3.56 (m, 1H), 3.43-3.34 (m,2H), 2.49 (s, 3H), 2.33 (s, 3H), 1.92 (d, J=13.3 Hz, 1H), 1.66 (d, J=3.8Hz, 7H), 1.42 (dd, J=4.3, 12.5 Hz, 1H), 0.98 (d, J=13.3 Hz, 1H). LCMS:RT=1.99 min; MS (ES): m/z=532.4 [M+H]⁺ (ACN/H₂O with HCOONH₄, AscentisExpress C18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLCRT=8.487 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=3.67 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=4.38 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 141 & 1422-{5-[(3,4-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl]-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(3,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted toracemic2-{5-[(3,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(90.0 mg, 49%), which was separated by chiral prep SFC (Column: LuxCellulose 4, 25×2.1 cm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA inMeOH); Flow: 60 mL/min) to give Enantiomer A (25.0 mg, 14%) andEnantiomer B (23.0 mg, 13%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ8.37 (d, J=2.0 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.15 (s, 1H), 8.05 (s,1H), 7.68-7.57 (m, 1H), 7.52-7.39 (m, 2H), 7.24 (td, J=8.5, 10.5 Hz,1H), 5.75 (s, 1H), 4.06-3.95 (m, 1H), 3.89-3.78 (m, 1H), 3.66-3.55 (m,1H), 3.40 (m, 2H), 2.49 (s, 3H), 2.33 (s, 3H), 1.92 (d, J=13.3 Hz, 1H),1.68 (d, J=3.5 Hz, 6H), 1.65-1.58 (m, 1H), 1.45-1.34 (m, 1H), 1.16-1.07(d, J=13.3 Hz, 1H). LCMS: RT=2.05 min; MS (ES): m/z=532.4 [M+H]⁺(ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm,gradient=4 min, wavelength=220 nm); HPLC RT=8.911 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=3.36 min (Column: Lux Cellulose 4, 250×4.6 mm, 5 μm;Mobile Phase: 55/45 CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min). EnantiomerB: Chiral SFC RT=3.89 min (Column: Lux Cellulose 4, 250×4.6 mm, 5 μm;Mobile Phase: 55/45 CO₂/(0.25% DEA in MeOH); Flow: 3 mL/min).

Examples 143 & 1442-{5-[(2,6-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl]-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,6-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted toracemic2-{5-[(2,6-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC (Column: Chiralcel OD-H, 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 70 mL/min)to give Enantiomer A (7.00 mg, 9%) and Enantiomer B (6.00 mg, 7%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.40 (d, J=1.5 Hz, 1H),8.29-8.20 (m, 2H), 8.08 (s, 1H), 7.55-7.50 (m, 1H), 7.45-7.35 (m, 1H),7.09-7.02 (m, 2H), 6.07 (d, J=11.5 Hz, 1H), 4.03 (d, J=9.0 Hz, 1H), 3.81(d, J=11.5 Hz, 1H), 3.61-3.50 (m, 1H), 3.45-3.35 (m, 2H), 2.53 (s, 3H),2.37 (s, 3H), 1.83 (d, J=14.1 Hz, 1H), 1.66 (s, 6H), 1.72-1.62 (m, 1H),1.42 (m, 1H), 1.06 (d, J=13.1 Hz, 1H). LCMS: RT=1.85 min; MS (ES):m/z=532.4 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm(50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=8.403 min(Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=2.62 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 55/45 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=3.66 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 55/45 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 145 & 1462-{5-[(2,3-Difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl]-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2,3-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted toracemic2-{5-[(2,3-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC (Column: Chiralcel OD-H, 25×2.1cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 70 mL/min)to give Enantiomer A (52.0 mg, 30%) and Enantiomer B (54.0 mg, 31%).Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, J=1.60 Hz, 1H), 8.26(d, J=8.40 Hz, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.89 (t, J=7.60 Hz, 1H),7.47 (d, J=8.00 Hz, 1H), 7.20-7.32 (m, 2H), 6.00 (d, J=12.00 Hz, 1H),3.99 (dd, J=3.20, 11.00 Hz, 1H), 3.80 (dd, J=2.80, 11.40 Hz, 1H), 3.60(dt, J=11.60, Hz, 1H), 3.33-3.40 (m, 2H), 2.48 (s, 3H), 2.32 (s, 3H),1.89-2.04 (m, 1H), 1.60-1.70 (m, 7H), 1.37-1.47 (m, 1H), 0.97 (d,J=12.80 Hz, 1H). LCMS: RT=2.013 min; MS (ES): m/z=532.5 [M+H]⁺ (ACN/H₂Owith HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm, gradient=4 min,wavelength=220 nm); HPLC RT=8.534 min (Column: Sunfire C18 3.5 μm,4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient 10-100%B over 15 min; Flow: 1 mL/min; Detection: UV at 220 nm). Chiral SFCRT=2.38 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase:55/45 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). Enantiomer B: Chiral SFCRT=2.96 min (Column: Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase:55/45 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Examples 147 & 1482-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(3-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl]-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(3-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted toracemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(3-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(110 mg, 48%), which was separated by chiral prep SFC (Column: ChiralcelOD-H, 25×2.1 cm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA in MeOH);Flow: 60 mL/min) to give Enantiomer A (30.0 mg, 13%) and Enantiomer B(30.0 mg, 13%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.36 (d, J=1.5Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.51-7.31(m, 4H), 7.06-6.98 (m, 1H), 5.77 (s, 1H), 4.04-3.97 (m, 1H), 3.82 (dd,J=2.5, 11.5 Hz, 1H), 3.66-3.56 (m, 1H), 3.47-3.40 (m, 2H), 2.49 (s, 3H),2.33 (s, 3H), 1.94 (d, J=13.1 Hz, 1H), 1.68 (d, J=3.0 Hz, 6H), 1.65-1.59(m, 1H), 1.46-1.38 (m, 1H), 1.16-1.08 (m, 1H). LCMS: RT=2.02 min; MS(ES): m/z=514.4 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=8.511 min(Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=3.28 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=5.06 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 65/35 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Examples 149 & 1502-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for the synthesis of2-{5-[(2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl]-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,(2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol was converted toracemic2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(70.0 mg, 70%), which was separated by chiral prep SFC (Column:Chiralcel OD-H, 25×2.1 cm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 70 mL/min) to give Enantiomer A (35.0 mg, 34%) andEnantiomer B (35.0 mg, 34%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ8.34-8.35 (m, 1H), 8.24 (d, J=8.00 Hz, 1H), 8.16 (s, 1H), 8.02-8.09 (m,2H), 7.43-7.46 (m, 1H), 7.28-7.36 (m, 2H), 7.03-7.08 (m, 1H), 5.94-5.97(m, 1H), 3.97-3.98 (m, 1H), 3.77-3.81 (m, 1H), 3.56-3.62 (m, 1H),3.30-3.39 (m, 2H), 2.47 (s, 3H), 2.31 (s, 3H), 1.88-1.93 (m, 1H),1.60-1.68 (m, 7H), 1.39-1.43 (m, 1H), 0.95-0.98 (m, 1H). LCMS: RT=2.28min; MS (ES): m/z=514.2 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis ExpressC18 2.7 μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLCRT=8.068 min (Column: Sunfire C18 3.5 μm, 4.6×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 10-100% B over 15 min; Flow:1 mL/min; Detection: UV at 220 nm). Chiral SFC RT=2.25 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 55/45 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min). Enantiomer B: Chiral SFC RT=3.59 min (Column:Chiralcel OD-H, 250×4.6 mm, 5 μm; Mobile Phase: 55/45 CO₂/(0.25% DEA inMeOH); Flow: 3 mL/min).

Example 151N-Cyclopropyl-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-9-carboxamide

Step 1: Methyl 2-(5-bromo-3-nitropyridin-2-yl)benzoate

In a 40 ml, vial was added a mixture of 2,5-dibromo-3-nitropyridine(2.00 g, 7.09 mmol), (2-(methoxycarbonyl)phenyl)boronic acid (1.41 g,7.80 mmol), and 2 M aqueous tripotassium phosphate (7.09 mL, 14.2 mmol)in tetrahydrofuran (20 mL), and the reaction mixture was purged under astream of nitrogen for several min. The mixture was then treated withPdCl₂(dppf)-CH₂Cl₂ adduct (0.290 g, 0.355 mmol), capped with a septum,evacuated, and purged with nitrogen 3 times. The reaction mixture wasthen heated in a heating block at 80° C. for 3 h. The reaction mixturewas diluted with water and extracted into ethyl acetate. The organicswere washed with water, and the volatiles were removed under reducedpressure to give a dark residue. The material was purified using silicagel column chromatography with an ISCO Companion (80 g silica gelcolumn) and eluted with an EtOAc/hexane gradient (10-50%) to give methyl2-(5-bromo-3-nitropyridin-2-yl)benzoate (1.10 g, 3.26 mmol, 46%) as alight-yellow residue that slowly solidified. LCMS: Waters Acquity SDS.Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8mL/min. Solvent A: H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1% TFA; LCMS:RT=0.92 min; (ES): m/z (M+H)⁺=337.0, 339.0.

Step 2: 3-Bromo-5H-pyrido[3,2-b]indole-9-carboxylate

A solution of methyl 2-(5-bromo-3-nitropyridin-2-yl)benzoate (1.00 g,2.97 mmol) and 1,3-bis(diphenylphosphino)propane (1.35 g, 3.26 mmol) in1,2-dichlorobenzene (10 mL) was sealed in a large 20 mL vial and heatedin a heating block at 155° C. overnight. The solvent was removed underhigh vacuum to give a dark residue, which was purified using silica gelcolumn chromatography with an ISCO Companion (80 g silica gel column)and eluted with a EtOAc/hexane gradient (20-50%) to give methyl3-bromo-5H-pyrido[3,2-b]indole-9-carboxylate (220 mg, 0.721 mmol, 24%).LCMS: Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad)2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA. LCMS: RT=0.60 min; (ES): m/z (M+H)⁺=305.0, 307.0.1H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=2.0 Hz, 1H), 8.40 (br. s., 1H),7.90 (s, 1H), 7.75 (dd, J=7.2, 1.2 Hz, 1H), 7.66-7.54 (m, 2H), 4.12 (s,3H).

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-9-carboxylate

A solution of methyl 3-bromo-5H-pyrido[3,2-b]indole-9-carboxylate (220mg, 0.721 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (334mg, 0.865 mmol), copper(I) iodide (27.5 mg, 0.144 mmol), Pd(Ph₃P)₄ (83.0mg, 0.0720 mmol), TEA (0.201 mL, 1.44 mmol), and DMF (5 mL) in a 20 mLvial was capped and heated in a heating block at 95° C. overnight. Thereaction mixture was diluted with NH₄OH (aq) and water and extractedinto ethyl acetate. The organics were washed with water and brine andconcentrated. The residue was purified using silica gel columnchromatography with an ISCO Companion (40 g silica gel column) andeluted with a MeOH/CH₂Cl₂ gradient (0-10%) to give methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-9-carboxylate(70.0 mg, 0.218 mmol, 30%). LCMS: Waters Acquity SDS. Column: BEH C182.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A:H₂O −0.1% TFA. Solvent B: Acetonitrile−0.1% TFA. LCMS: RT=0.56 min;(ES): m/z (M+H)⁺=322.2.

Step 4. (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-9-carboxylate

A solution of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-9-carboxylate(70.0 mg, 0.218 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(84.0 mg, 0.436 mmol), and triphenylphosphine (114 mg, 0.436 mmol) indichloromethane (4 mL) was treated drop wise with DIAD (0.0850 mL, 0.436mmol), and the mixture was stirred at room temperature overnight. Themixture was directed loaded onto a silica gel column. The material waspurified using silica gel column chromatography using an ISCO Companion(40 g silica gel column) and eluted with a MeOH/CH₂Cl₂ gradient (0-10%).The fractions that contained product were collected, and the volatileswere removed to give a yellow oil, which was purified a second time onan ISCO Companion (24 g silica gel column) and eluted with ethyl acetateto give (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-9-carboxylate(35.0 mg, 35%). LCMS: Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA.Solvent B: Acetonitrile−0.1% TFA; LCMS: RT=0.74 min; (ES): m/z(M+H)⁺=496.3. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.33 (br. s.,1H), 7.96 (s, 1H), 7.67 (d, J=7.4 Hz, 3H), 7.45 (d, J=7.4 Hz, 1H),7.37-7.30 (m, 2H), 7.28-7.21 (m, 1H), 5.90 (d, J=11.1 Hz, 1H), 4.02 (br.s., 2H), 3.95 (s, 3H), 3.91 (d, J=9.4 Hz, 1H), 3.72 (d, J=9.4 Hz, 1H),3.52-3.38 (m, 2H), 3.27 (t, J=11.3 Hz, 1H), 2.30 (br. s., 3H), 1.73 (d,J=13.1 Hz, 1H), 1.61-1.51 (m, 1H), 1.36-1.25 (m, 1H), 0.97 (d, J=12.5Hz, 1H).

Step 5:N-Cyclopropyl-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-9-carboxamide

A solution of (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-9-carboxylate(35.0 mg, 0.0710 mmol) in methanol (2 mL) was treated with 1 N NaOH(0.706 mL, 0.706 mmol), and the light-yellow solution was stirred atroom temperature. The mixture was concentrated on a rotary evaporator toobtain a solid residue. This was treated with 1 N HCl and dissolved in 2mL of methanol, and the solution was concentrated on a rotary evaporatorto give of(S)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-9-carboxylicacid (34.0 mg, 0.0710 mmol) as a white solid, which was used withoutpurification. LCMS: Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u(1.6 min grad) 2-98% B. Flow Rate=0.8 ml/min. Solvent A: H₂O−0.1% TFA.Solvent B: Acetonitrile−0.1% TFA. LCMS: RT=0.80 min; (ES): m/z(M+H)⁺=482.3.

A solution of(S)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-9-carboxylicacid (34.0 mg, 0.0710 mmol) in DMF (2 mL) was treated with EDC (27.1 mg,0.141 mmol), HOBT (21.6 mg, 0.141 mmol), and then with cyclopropylamine(20.2 mg, 0.353 mmol), and the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with water and 1 N HCl. Theaqueous layer was extracted with ethyl acetate, and the organics werewashed with water and concentrated. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-55% B over 25 min, then a5-min hold at 55% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveN-cyclopropyl-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-9-carboxamide(6.00 mg, 16%). LCMS: RT=1.72 min; (ES): m/z (M+H)⁺=521.3 (Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). ¹H NMR (500 MHz, DMSO-d₆) δ 12.17 (d, J=3.7 Hz, 1H), 8.68(br. s., 1H), 8.64-8.36 (m, 1H), 8.15 (d, J=6.1 Hz, 1H), 7.96 (s, 1H),7.76 (br. s., 1H), 7.67 (d, J=7.7 Hz, 2H), 7.40-7.30 (m, 2H), 7.29-7.21(m, 1H), 5.99 (d, J=11.1 Hz, 1H), 4.03 (br. s., 3H), 3.90 (d, J=8.8 Hz,1H), 3.71 (d, J=9.1 Hz, 1H), 3.49 (d, J=11.1 Hz, 1H), 3.42-3.35 (m, 1H),3.25 (t, J=11.4 Hz, 1H), 3.07 (td, J=7.2, 3.9 Hz, 1H), 2.31 (br. s.,3H), 1.76 (d, J=11.4 Hz, 1H), 1.66-1.52 (m, 1H), 1.36-1.24 (m, 1H), 0.91(d, J=10.1 Hz, 1H), 0.83 (d, J=7.1 Hz, 2H), 0.73 (br. s., 2H).

Example 152[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-6-yl]methanol

Step 1: Methyl 3-(5-bromo-3-nitropyridin-2-yl)-4-fluorobenzoate

A mixture of 2,5-dibromo-3-nitropyridine (705 mg, 2.50 mmol) and(2-fluoro-5-(methoxycarbonyl)phenyl)boronic acid (495 mg, 2.50 mmol) intetrahydrofuran (10 mL) in a 20 mL vial was purged under a stream ofnitrogen and then treated with 2 M aqueous tripotassium phosphate (3.75mL, 7.50 mmol) (solids formed) and then with PdCl₂(dppf)-CH₂Cl₂ adduct(204 mg, 0.250 mmol). The vial was capped with a septum, evacuated, andpurged with nitrogen 3 times before the reaction mixture was heated in aheating block to 80° C. Note—the solids gradually dissolved on heating.After 3 h, the mixture was cooled to room temperature, diluted withwater, and extracted into ethyl acetate. The organics were washed withwater, and the volatiles were removed under reduced pressure to give adark residue. The material was purified using silica gel columnchromatography with an ISCO Companion (80 g silica gel column) andeluted with EtOAc/hexane gradient (10-40%) to give methyl3-(5-bromo-3-nitropyridin-2-yl)-4-fluorobenzoate (507 mg, 1.43 mmol,57%) as a white crystalline solid. LCMS: Waters Acquity SDS. Column: BEHC18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min.Solvent A: H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1% TFA. LCMS: RT=0.99min; (ES): m/z (M+H)⁺=355.0, 356.9. ¹H NMR (400 MHz, CDCl₃) δ 8.99 (d,J=2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.39 (dd, J=7.0, 2.2 Hz, 1H),8.18 (ddd, J=8.7, 5.1, 2.3 Hz, 1H), 7.18 (dd, J=9.7, 8.8 Hz, 1H), 3.94(s, 3H).

Step 2: Methyl 3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-6-carboxylate

A mixture of methyl 3-(5-bromo-3-nitropyridin-2-yl)-4-fluorobenzoate(500 mg, 1.41 mmol) and 1,2-bis(diphenylphosphino)ethane (701 mg, 1.76mmol) in 1,2-dichlorobenzene (5 mL) was capped in a 20 mL vial andheated in a heating block at 170° C. for 5 h. The reaction mixture wasremoved from the heating block, and the dark mixture was transferred toa RB flask and concentrated under high vacuum. The resulting blackresidue was dissolved in DCM and purified using silica gel columnchromatography with an ISCO Companion (40 g silica gel column) andeluted with EtOAc/hexane gradient (15-50%) to give methyl3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-6-carboxylate (170 mg, 0.526mmol, 37%) as a white solid. LCMS: Waters Acquity SDS. Column: BEH C182.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A:H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1% TFA. LCMS: RT=0.93 min; (ES):m/z (M+H)¹=323.0, 325.0.

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-6-carboxylate

In a 20 mL vial was added a mixture of1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (264 mg, 0.684 mmol),methyl 3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-6-carboxylate (170 mg,0.526 mmol), copper(I) iodide (20.0 mg, 0.105 mmol), and TEA (0.147 mL,1.05 mmol) in DMF (5 mL), and the mixture was purged under a stream ofnitrogen. Then was added Pd(Ph₃P)₄ (60.8 mg, 0.0530 mmol) and cappedwith a septum. The vial was evacuated and purged with nitrogen 3 timesand then the reaction mixture was heated in a heating block at 95° C.for 3 h. The mixture was cooled to room temperature, diluted with waterand aqueous ammonium hydroxide, and extracted into ethyl acetate. Theorganics were washed with water and brine, and the volatiles wereremoved. The resulting residue was dissolved in DCM and purified usingsilica gel column chromatography with an ISCO Companion (24 g silica gelcolumn) and eluted with ethyl acetate to give methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-6-carboxylate(160 mg, 0.292 mmol, 56%) as an off-white solid. LCMS: Waters AcquitySDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. FlowRate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1%TFA. LCMS: RT=0.75 min; (ES): m/z (M+H)⁺=340.1.

Step 4. (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-6-carboxylate

In a 20 mL vial was added methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-6-carboxylate(160 mg, 0.472 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (181mg, 0.943 mmol) and dichloromethane (6 mL), and the reaction mixture wasthen treated with triphenylphosphine (247 mg, 0.943 mmol) and wastreated drop wise with DIAD (0.183 mL, 0.943 mmol). The reaction mixturewas stirred at room temperature overnight. The crude reaction mixturewas directly loaded onto a silica gel column and was purified using anISCO Companion (40 g silica gel column) with ethyl acetate to give(S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-6-carboxylate(150 mg, 60%) as a white solid. LCMS4: Waters Acquity SDS. Column: BEHC18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min.Solvent A: H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1% TFA. LCMS: RT=0.92min; (ES): m/z (M+H)⁺=514.2.

Step 5:[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-6-yl]methanol

A solution of (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-6-carboxylate(40.0 mg, 0.0780 mmol) in tetrahydrofuran (5 mL) in a 20 mL vial wascooled in an ice bath and treated with solid LiAlH₄ (5.91 mg, 0.156mmol), and the mixture was stirred in the bath. After 1 h, more LiAlH₄(5.91 mg, 0.156 mmol) was added. After 2 h the mixture was quenched withsat. aq. ammonium chloride and extracted into ethyl acetate. Theorganics were washed with water, and the volatiles were removed underreduced pressure to give a white solid. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over25 min, then a 5-min hold at 55% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give[3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-6-yl]methanol(8.00 mg, 20%). LCMS: RT 1.39 min; (ES): m/z (M+H)⁺=486.2 (Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). ¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (s, 1H), 7.96 (s, 1H),7.67 (d, J=7.7 Hz, 2H), 7.64-7.58 (m, 1H), 7.36-7.31 (m, 2H), 7.28-7.22(m, 1H), 7.11 (t, J=8.8 Hz, 1H), 6.41 (d, J=11.1 Hz, 1H), 5.10-5.04 (m,2H), 3.92-3.87 (m, 1H), 3.84 (s, 3H), 3.71 (d, J=8.4 Hz, 1H), 3.55-3.40(m, 2H), 3.23 (t, J=11.4 Hz, 1H), 2.16 (s, 3H), 1.92 (m, 1H), 1.60-1.44(m, 2H), 0.70 (d, J=12.8 Hz, 1H).

Example 1534-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]-2-methylbutan-2-ol

Step 1: Methyl 3-(3-(5-bromo-3-nitropyridin-2-yl)phenyl)propanoate

Following a procedure analogous to that described for the synthesis ofmethyl 3-(5-bromo-3-nitropyridin-2-yl)-4-fluorobenzoate,2,5-dibromo-3-nitropyridine (1084 mg, 3.85 mmol) and(3-(3-methoxy-3-oxopropyl)phenyl)boronic acid (800 mg, 3.85 mmol) wereconverted to methyl 3-(3-(5-bromo-3-nitropyridin-2-yl)phenyl)propanoate(700 mg, 1.92 mmol, 50%) as a light-yellow, thick oil. LCMS: RT=1.00min; (ES): m/z (M+H)⁺=365.0, 367.0. (LCMS: Waters Acquity SDS. Column:BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min.Solvent A: H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1% TFA). ¹H NMR (400MHz, CDCl₃) δ 8.91 (d, J=2.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 7.45-7.31(m, 4H), 3.69 (s, 3H), 3.02 (t, J=7.7 Hz, 2H), 2.67 (t, J=7.8 Hz, 2H).

Step 2: Methyl 3-(3-bromo-5H-pyrido[3,2-b]indol-6-yl)propanoate

Following a procedure analogous to that described for the synthesis ofmethyl 3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-6-carboxylate, methyl3-(3-(5-bromo-3-nitropyridin-2-yl)phenyl)propanoate (700 mg, 1.92 mmol)was converted to methyl 3-(3-bromo-5H-pyrido[3,2-b]indol-6-yl)propanoate(280 mg, 0.840 mmol, 44%) as white solid. LCMS: RT=0.83 min; (ES): m/z(M+H)⁺=333.0, 335.0 (Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u(1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA.Solvent B: Acetonitrile−0.1% TFA). ¹H NMR (400 MHz, CDCl₃) δ 9.21 (br.s., 1H), 8.60 (d, J=2.0 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.38-7.34 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 3.69 (s, 3H),3.32-3.22 (m, 2H), 2.88-2.78 (m, 2H). Also obtained from the reactionwas the isomeric methyl 3-(3-bromo-5H-pyrido[3,2-b]indol-8-yl)propanoate(210 mg, 0.630 mmol, 33%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.60 (d, J=2.0 Hz, 1H), 8.18-8.16 (m, 1H), 8.06 (br. s., 1H), 7.88 (d,J=2.0 Hz, 1H), 7.44-7.39 (m, 2H), 3.69 (s, 3H), 3.17 (t, J=7.8 Hz, 2H),2.81-2.71 (m, 2H). LCMS: RT=0.79 min; (ES): m/z (M+H)⁺=333.0, 335.0(Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad)2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA).

Step 3: (S)-Methyl3-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-8-yl)propanoate

Following a procedure analogous to that described in steps 3 and 4 forthe synthesis of (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-6-carboxylate,methyl 3-(3-bromo-5H-pyrido[3,2-b]indol-8-yl)propanoate (210 mg, 0.630mmol) was converted to (S)-methyl3-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-8-yl)propanoate(33.0 mg, 18%). LCMS: RT=0.86 min; (ES): m/z (M+H)⁺=524.3 (WatersAcquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B.Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA). 1H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.07(m, 2H), 7.95 (s, 1H), 7.66 (d, J=7.4 Hz, 2H), 7.50 (d, J=7.4 Hz, 1H),7.37-7.27 (m, 2H), 7.27-7.17 (m, 1H), 5.77 (d, J=11.4 Hz, 1H), 4.01 (br.s., 3H), 3.88 (d, J=13.8 Hz, 1H), 3.72 (d, J=8.8 Hz, 1H), 3.58 (s, 3H),3.48-3.34 (m, 2H), 3.27 (t, J=11.3 Hz, 1H), 3.05 (t, J=7.4 Hz, 2H),2.80-2.68 (m, 2H), 2.30 (s, 3H), 1.67 (d, J=12.5 Hz, 1H), 1.60-1.45 (m,1H), 1.37-1.19 (m, 1H), 1.00 (d, J=12.5 Hz, 1H).

Step 4:4-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]-2-methylbutan-2-ol

Following a procedure analogous to that described for the synthesis of(S)-2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,(S)-methyl3-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-8-yl)propanoatewas converted to4-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]-2-methylbutan-2-ol.¹H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.04 (s, 2H), 7.94 (s, 1H),7.66 (d, J=7.7 Hz, 2H), 7.47 (d, J=7.4 Hz, 1H), 7.37-7.27 (m, 2H),7.27-7.17 (m, 1H), 5.76 (d, J=11.1 Hz, 1H), 4.01 (br. s., 3H), 3.88 (d,J=13.5 Hz, 1H), 3.72 (d, J=9.4 Hz, 1H), 3.55-3.36 (m, 2H), 3.27 (t,J=11.3 Hz, 1H), 2.85-2.76 (m, 2H), 2.30 (s, 3H), 1.79-1.71 (m, 2H), 1.67(d, J=12.5 Hz, 1H), 1.58-1.46 (m, 1H), 1.35-1.24 (m, 1H), 1.18 (s, 6H),1.01 (d, J=12.1 Hz, 1H). LCMS: RT=1.75 min; (ES): m/z (M+H)⁺=524.35(LCMS: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min).

Examples 154 & 1554-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Step 1:3-Bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole

In a 20 mL vial was added a mixture of3-bromo-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole (300 mg, 0.923 mmol),(4,4-difluorocyclohexyl)(phenyl)methanol (417 mg, 1.85 mmol), andtriphenylphosphine (484 mg, 1.85 mmol), and dichloromethane (10 mL), andthe mixture was stirred at room temperature while treated drop wise withDIAD (0.359 mL, 1.85 mmol), and then stirred at room temperature. Thesuspension gradually became a solution during the addition. After 5 h,the mixture was loaded onto a silica gel column and purified usingsilica gel column chromatography, using an ISCO Companion (120 g silicagel column) and eluted with a EtOAc/hexane gradient (20-0%) to give3-bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole(492 mg, 0.922 mmol, 100%). LCMS: RT=1.06 min; (ES): m/z (M+H)⁺=533.0,535.0. (Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 mingrad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA).

Step 2:4-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

In a 2 dram vial was added a mixture of3-bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole(150 mg, 0.281 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(94.0 mg, 0.422 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (34.4 mg, 0.0420 mmol),2 M aqueous tripotassium phosphate (0.422 mL, 0.844 mmol), andtetrahydrofuran (3 mL). The mixture was purged with a nitrogen stream.The vial was capped and heated in a heating block at 90° C. 3 h. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 25-100% B over 20 min, then a 5-min hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to give racemic4-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole,which was separated by chiral prep HPLC (Chiralcel OD 20×250 mm 20mL/min 15% EtOH/0.5% DEA in Heptane) to give Enantiomer A (5.00 mg, 3%)and Enantiomer B (4.00 mg, 3%). Enantiomer A: ¹H NMR (500 MHz, DMSO-d₆)δ 8.76 (br. s., 1H), 8.59 (s, 1H), 8.46 (d, J=8.2 Hz, 1H), 8.38 (br. s.,1H), 7.85 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.7 Hz, 2H), 7.38-7.31 (m, 2H),7.30-7.22 (m, 1H), 6.05 (d, J=11.3 Hz, 1H), 3.39 (s, 3H), 2.49 (s, 3H),2.31 (s, 3H), 2.17-1.97 (m, 3H), 1.92 (br. s., 2H), 1.84-1.68 (m, 1H),1.64 (br. s., 1H), 1.37 (d, J=13.4 Hz, 1H), 1.28-1.13 (m, 1H). LCMS:RT=1.98 min; (ES): m/z (M+H)⁺=550.1. (Column: Waters Acquity UPLC BEHC18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). Chiral HPLC: RT=11.761 min (Column: Chiralcel OD 250×4.6mm, 5 μm; Mobile Phase: 20% Ethanol (0.1% DEA) in Heptane (0.1 5 DEA);Flow: 1 mL/min). Enantiomer A: Chiral HPLC: RT=13.669 min(Column:Chiralcel OD 250×4.6 mm, 5 μm; Mobile Phase: 20% Ethanol (0.1% DEA) inheptane (0.1 5 DEA); Flow: 1 mL/min).

Examples 156 & 1575-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

In a 2 dram vial was added a mixture of3-bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole(150 mg, 0.281 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole(163 mg, 0.422 mmol), copper(I) iodide (10.7 mg, 0.0560 mmol), Pd(Ph₃P)₄(32.5 mg, 0.0280 mmol), and DMF (2 mL). The mixture was treated withEt₃N (0.118 mL, 0.844 mmol) and purged with a nitrogen stream. The vialwas capped and heated in a heating block at 90° C. for 4 h and wasfiltered through a 0.45 um nylon membrane filter, and the crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×200 mm, 5-μm; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-70% B over20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified on chiral prep SFC(Column: Chiral ID 25×3 cm, 5 μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 85mL/min) to give5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazoleEnantiomer A (20.0 mg, 13%) and Enantiomer B (20.0 mg 13%). EnantiomerA: ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (br. s., 1H), 8.67 (s, 1H),8.58-8.53 (m, 1H), 8.50 (d, J=8.2 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.67(d, J=7.6 Hz, 2H), 7.41-7.31 (m, 2H), 7.30-7.22 (m, 1H), 6.06 (d, J=11.0Hz, 1H), 4.02 (s, 3H), 3.39 (br. s., 3H), 2.30 (s, 3H), 2.16-1.98 (m,2H), 1.91 (br. s., 2H), 1.83-1.53 (m, 3H), 1.38 (d, J=11.9 Hz, 1H), 1.23(br. s., 1H). LCMS: RT=1.742 min; (ES): m/z (M+H)⁺=550.15 (Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). Chiral SFC RT=7.50 min (Column: Chiralcel ID 250×4.6 mm, 5μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ChiralSFC RT=8.50 min (Column: Chiralcel ID 250×4.6 mm, 5 μm; Mobile Phase:70/30 CO₂/MeOH; Flow: 2 mL/min).

Examples 158 & 1595-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following a procedure analogous to that described for the synthesis of5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole and3-bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indolewere converted, after chiral prep SFC (Column: Chiral ID 25×3 cm, 5 μm;Mobile Phase: 70/30 CO₂/MeOH; Flow: 85 mL/min), to 5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazoleEnantiomer A (16.0 mg, 10%) and Enantiomer B (17.0 mg 11%). EnantiomerA: ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (br. s., 1H), 8.67 (s, 1H),8.59-8.52 (m, 1H), 8.50 (d, J=8.2 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.66(d, J=7.6 Hz, 2H), 7.42-7.31 (m, 2H), 7.31-7.22 (m, 1H), 6.06 (d, J=11.3Hz, 1H), 4.02 (s, 3H), 3.39 (s, 3H), 2.16-1.98 (m, 3H), 1.91 (br. s.,2H), 1.83-1.67 (m, 1H), 1.65-1.52 (m, 1H), 1.38 (d, J=12.0 Hz, 1H), 1.23(br. s., 1H). LCMS: RT=1.736 min; (ES): m/z (M+H)⁺=553.10 (Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). Chiral SFC RT=7.50 min (Column: Chiralcel ID 250×4.6 mm, 5μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ChiralSFC RT=8.50 min (Column: Chiralcel ID 250×4.6 mm, 5 μm; Mobile Phase:70/30 CO₂/MeOH; Flow: 2 mL/min).

Example 1605-{6,7-Difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Step 1: (2-Bromo-4,5-difluorophenyl)(methyl)sulfane

In a 40 mL vial, a solution of 1-bromo-2,4,5-trifluorobenzene (2.00 g,9.48 mmol) in DMSO (15 mL) was treated with NaSMe (3.32 g, 47.4 mmol),and the resulting suspension stirred at room temperature for 4 h. Thereaction mixture was diluted with DCM, and the organics were washed withwater and brine. The volatiles were concentrated to give(2-bromo-4,5-difluorophenyl)(methyl)sulfane (2.20 g, 98%), which wasused without further purification in next reaction. ¹H NMR (400 MHz,CDCl₃) δ 7.23 (dd, J=8.7, 5.7 Hz, 1H), 6.98 (dd, J=8.5, 6.4 Hz, 1H),2.46 (s, 3H). HPLC: RT=2.756 min; (Chromolith ODS S5 4.6×50 mm (4 mingrad) 0-100% B. Flow Rate=4 ml/min. Inj. Vol.=10 uL. Wavelength=220.Oven Temp.=40° C. Solvent A: 10% MeOH−90% H₂O−0.1% TFA. Solvent B: 90%MeOH−10% H₂O−0.1% TFA).

Step 2: 1-Bromo-4,5-difluoro-2-(methylsulfonyl)benzene

A solution of (2-bromo-4,5-difluorophenyl)(methyl)sulfane (2.20 g, 9.20mmol) in 2-propanol (50 mL) in a RB flask was treated with Oxone (11.3g, 18.4 mmol), and the suspension was stirred vigorously and dilutedwith some water to dissolve some of the Oxone solids to give a whitemilky suspension, which was stirred at room temperature and stirredovernight. The mixture was diluted with water and extracted into DCM,and the combined organics were concentrated to give1-bromo-4,5-difluoro-2-(methylsulfonyl)benzene (2.40 g, 8.85 mmol, 96%)as a white solid. HPLC: RT=1.362 min; (Chromolith ODS S5 4.6×50 mm (4min grad) 0-100% B. Flow Rate=4 ml/min. Inj. Vol.=10 uL. Wavelength=220.Oven Temp.=40° C. Solvent A: 10% MeOH−90% H₂O−0.1% TFA. Solvent B: 90%MeOH−10% H₂O−0.1% TFA). LCMS: RT=0.79 min; (ES): m/z (M+H)⁺=270.8,272.9. (Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 mingrad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (dd, J=7.1, 5.7Hz, 1H), 7.55 (dd, J=8.4, 5.0 Hz, 1H), 3.25 (d, J=0.6 Hz, 3H).

Step 3:2-(4,5-Difluoro-2-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

In a large 40 mL vial was added a mixture of1-bromo-4,5-difluoro-2-(methylsulfonyl)benzene (2.40 g, 8.85 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.70 g,10.6 mmol), potassium acetate (2.61 g, 26.6 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (0.362 g, 0.443 mmol) in dioxane (20 mL). The vialwas capped and heated in heating block at 90° C. overnight. Diluted withwater and extracted into ethyl acetate. The organics were washed withwater, and the volatiles were removed under reduced pressure and theresulting black residue was dissolve in DCM and purified using silicagel column chromatography with an ISCO Companion 40 g silica gel columnand eluted with an EtOAc/hexane gradient (50-100%) to give2-(4,5-difluoro-2-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.1 g, 6.60 mmol, 74.6%) as a yellow slowly solidifying residue. ¹H NMR(400 MHz, CDCl₃) δ 7.69-7.58 (m, 2H), 3.25 (d, J=0.6 Hz, 3H), 1.41-1.37(m, 12H). LCMS: RT=0.54 min; (ES): m/z (M+H)⁺=237.1 (boronic acid)(Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad)2-98% B. Flow Rate=0.8 ml/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA).

Step 4:5-Bromo-2-(4,5-difluoro-2-(methylsulfonyl)phenyl)-3-nitropyridine

In a 40 ml vial was added a mixture of 2,5-dibromo-3-nitropyridine(1.861 g, 6.60 mmol),2-(4,5-difluoro-2-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.1 g, 6.60 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.404 g, 0.495 mmol), and2 Molar aqueous tripotassium phosphate (9.90 mL, 19.8 mmol), and themixture was purged under a stream of nitrogen. The vial was capped andheated in a heating block at 80° C. for 3 h. Diluted with water andextracted into ethyl acetate. The organics were washed with water andbrine and concentrated to give a black residue that was purified usingsilica gel column chromatography with an ISCO Companion 120 g silica gelcolumn and eluted with CH₂Cl₂/EtOAc gradient (0-50%) to give5-bromo-2-(4,5-difluoro-2-(methylsulfonyl)phenyl)-3-nitropyridine (1.2g, 3.05 mmol, 46.2%) as a light-yellow solid. LCMS: RT=0.90 min; (ES):m/z (M+H)⁺=392.7, 394.7. (Waters Acquity SDS. Column: BEH C18 2.1×50 mm1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 ml/min. Solvent A: H₂O−0.1%TFA. Solvent B: Acetonitrile−0.1% TFA) ¹H NMR (400 MHz, CDCl₃) δ 9.04(d, J=2.0 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 7.76 (dd, J=8.6, 5.3 Hz, 1H),7.63 (dd, J=9.2, 5.1 Hz, 1H), 3.32 (d, J=0.5 Hz, 3H).

Step 5: 3-Bromo-6,7-difluoro-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole

A solution of5-bromo-2-(4,5-difluoro-2-(methylsulfonyl)phenyl)-3-nitropyridine (1.2g, 3.05 mmol) and 1,2-bis(diphenylphosphino)ethane (1.459 g, 3.66 mmol)in 1,2-dichlorobenzene (15 mL) in a 40 mL vial was capped and heated ina heating block at 170° C. for 5 h. The solvents were evaporated on arotary evaporator with heating under high vacuum, and the residue waspurified using silica gel column chromatography with an ISCO Companion(120 g silica gel column) and eluted with an CH₂Cl₂/EtOAc gradient(20-70%) to give3-bromo-6,7-difluoro-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole (230 mg,0.637 mmol, 21%) as a light-yellow solid. LCMS: RT=0.81 min; (ES): m/z(M+H)⁺=360.9, 362.9. (Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA.Solvent B: Acetonitrile−0.1% TFA). ¹H NMR (400 MHz, CDCl₃) δ 8.70 (d,J=2.0 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.44 (dd, J=8.8, 4.2 Hz, 1H),3.33 (s, 3H).

Step 6:(S)-3-Bromo-6,7-difluoro-9-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

In a RB flask was added a suspension of3-bromo-6,7-difluoro-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole (230 mg,0.637 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (245 mg,1.27 mmol) in dichloromethane (6 mL), and the resulting reaction mixturewas treated with triphenylphosphine (334 mg, 1.27 mmol) before the dropwise addition of DIAD (0.248 mL, 1.27 mmol) at room temperature. Themixture was stirred at room temperature overnight. The material waspurified using silica gel column chromatography with an ISCO Companion(80 g silica gel column) and eluted with an CH₂Cl₂/EtOAc gradient(0-100%) to give(S)-3-bromo-6,7-difluoro-9-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(315 mg, 0.588 mmol, 92%) as a light-yellow solid. LCMS: RT=1.01 min;(ES): m/z (M+H)⁺=534.9, 536.9. (Waters Acquity SDS. Column: BEH C182.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A:H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1% TFA).

Step 7:5-{6,7-Difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

In a 2 dram vial was added a mixture of(S)-3-bromo-6,7-difluoro-9-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(30.0 mg, 0.0560 mmol),1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (32.5 mg, 0.0840mmol), copper(I) iodide (2.13 mg, 0.0110 mmol), Pd(Ph₃P)₄ (6.47 mg, 5.60μmol), and TEA (0.0230 mL, 0.168 mmol) in DMF (1 mL). The vial wascapped and heated in a heating block at 80° C. overnight. The reactionmixture was then diluted with ammonium hydroxide and water and extractedinto ethyl acetate. The organics were washed with water and brine, andthe organics were concentrated. The material was purified using silicagel column chromatography with an ISCO Companion (24 g silica gelcolumn) and eluted with ethyl acetate. The fractions containing productwere collected, and the volatiles were removed to give 15.0 mg of awhite solid. This material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-70% B over 20 min, then a 5-min hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give5-{6,7-difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole(5.10 mg, 16%). LCMS: RT=1.605 min; (ES): m/z (M+H)⁺=552.10; (Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min) ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (br. s., 1H), 8.34 (br.s., 1H), 7.69 (br. s., 2H), 7.51 (br. s., 1H), 7.38 (br. s., 2H), 7.31(d, J=6.9 Hz, 1H), 5.97 (br. s., 1H), 3.97-3.86 (m, 4H), 3.76 (d, J=9.6Hz, 1H), 3.63-3.45 (m, 5H), 3.28 (t, J=10.6 Hz, 1H), 2.22 (br. s., 3H),1.83 (br. s., 1H), 1.39 (br. s., 2H), 1.04 (d, J=12.2 Hz, 1H).

Example 1615-{6,7-Difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following a procedure analogous to that described for the synthesis of5-{6,7-difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,(S)-3-bromo-6,7-difluoro-9-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indoleand 4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole wereconverted to5-{6,7-difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.LCMS: RT=1.634 min; (ES): m/z (M+H)⁺=555.10; (Column: Waters AcquityUPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (br. s., 1H), 8.37 (br.s., 1H), 7.71 (br. s., 2H), 7.52 (br. s., 1H), 7.38 (br. s., 2H), 7.32(d, J=7.1 Hz, 1H), 5.98 (br. s., 1H), 4.01-3.85 (m, 4H), 3.77 (d, J=10.3Hz, 1H), 3.60-3.41 (m, 5H), 3.34-3.22 (m, 1H), 1.81 (br. s., 1H), 1.40(br. s., 2H), 1.05 (d, J=12.3 Hz, 1H).

Example 1625-{9-Methanesulfonyl-6,7-dimethoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

In a 2 dram vial, a mixture of5-{6,7-difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(10.0 mg, 0.0180 mmol) and KOtBu (10.1 mg, 0.0900 mmol) in methanol (1mL) was heated in a heating block at 90° C. overnight. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge Shield RP18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 15-100% B over 20 min, then a 5-min hold at 100% B;Flow: 20 mL/min. Fractions containing the product were combined anddried via centrifugal evaporation to give5-{9-methanesulfonyl-6,7-dimethoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(4.40 mg, 40%). LCMS: RT=1.605 min; (ES): m/z (M+H)⁺=579.2. (Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min). LCMS: RT=0.81 min; (ES): m/z (M+H)⁺=579.2 (Waters AcquitySDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. FlowRate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B: Acetonitrile−0.1%TFA). ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.14 (br. s., 1H), 7.61(d, J=7.5 Hz, 2H), 7.36-7.29 (m, 2H), 7.26 (d, J=7.6 Hz, 2H), 6.26 (d,J=10.9 Hz, 1H), 4.16 (s, 3H), 4.06 (s, 3H), 3.94-3.84 (m, 4H), 3.77 (d,J=9.3 Hz, 1H), 3.47 (br. s., 5H), 3.34 (t, J=11.3 Hz, 1H), 1.80 (d,J=12.5 Hz, 1H), 1.45 (d, J=12.1 Hz, 2H), 1.11 (d, J=12.1 Hz, 1H).

Example 1635-{7-Fluoro-9-methanesulfonyl-6-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

In a 2 dram vial, a mixture of5-{6,7-difluoro-9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(13.0 mg, 0.0230 mmol) and KOtBu (22.0 mg, 0.200 mmol) in methanol (2mL) was stirred at room temperature for 11 days. The resulting whitesuspension was diluted with water and HCl and extracted into ethylacetate. The organics were washed with water, and the volatiles wereremoved under reduced pressure to give a white solid. The material waspurified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-65% B over5 min, then a 20-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give5-{7-fluoro-9-methanesulfonyl-6-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(8.50 mg, 44%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.18 (s, 1H),7.62 (d, J=7.7 Hz, 2H), 7.53 (d, J=8.9 Hz, 1H), 7.39-7.29 (m, 2H),7.29-7.19 (m, 1H), 6.24 (d, J=10.9 Hz, 1H), 4.19 (s, 3H), 3.93-3.83 (m,4H), 3.76 (d, J=9.9 Hz, 1H), 3.66-3.52 (m, 2H), 3.49 (s, 3H), 3.33 (t,J=11.1 Hz, 1H), 1.80 (d, J=12.4 Hz, 1H), 1.50-1.36 (m, J=12.1, 12.1 Hz,2H), 1.10 (d, J=12.5 Hz, 1H). LCMS: RT=1.696 min; (ES): m/z (M+H)⁺=567.1(Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min).

Example 1645-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-6,7-difluoro-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(Enantiomer A)

Step 1:3-Bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-6,7,9-trifluoro-5H-pyrido[3,2-b]indole

In a 20 mL vial was added a suspension of3-bromo-6,7,9-trifluoro-5H-pyrido[3,2-b]indole (400 mg, 1.33 mmol),(4,4-difluorocyclohexyl)(phenyl)methanol (601 mg, 2.66 mmol), andtriphenylphosphine (697 mg, 2.66 mmol), and dichloromethane (6 mL). Themixture was stirred during drop-wise addition of DIAD (0.517 mL, 2.66mmol), and the mixture was stirred at room temperature overnight. Thereaction mixture was loaded onto a silica gel column and purified usingsilica gel column chromatography with an ISCO Companion (80 g silica gelcolumn) and eluted with an EtOAc/hexane gradient (10-50%) to give3-bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-6,7,9-trifluoro-5H-pyrido[3,2-b]indole(300 mg, 0.589 mmol, 44%) as a white solid. LCMS: RT=1.22 min; (ES): m/z(M+H)⁺=509.0, 511.0. (Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA.Solvent B: Acetonitrile−0.1% TFA).

Step 2:5-{-[(4,4-Diflurocyclohexyl)(phenyl)methyl]-6,7,9-trifluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

In a 20 mL vial was added a mixture of3-bromo-5-((4,4-difluorocyclohexyl)(phenyl)methyl)-6,7,9-trifluoro-5H-pyrido[3,2-b]indole(300 mg, 0.589 mmol),4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (344 mg,0.884 mmol), copper(I) iodide (22.4 mg, 0.118 mmol), and Pd(Ph₃P)₄ (68.1mg, 0.0590 mmol) in DMF (6 mL). The mixture was purged under a stream ofnitrogen for a few min and then was added Et₃N (0.246 mL, 1.767 mmol),and the vial was capped and heated in a heating block at 90° C. for 3 h.The reaction mixture was cooled to room temperature and diluted with aq.ammonium hydroxide and water and extracted into ethyl acetate. Theorganics were washed with water and brine and concentrated. The materialwas purified using silica gel column chromatography with an ISCOCompanion (40 g silica gel column) and eluted with an EtOAc/hexanegradient (50-100%) to give5-{-[(4,4-difluorocyclohexyl)(phenyl)methyl]-6,7,9-trifluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(230 mg, 0.435 mmol, 74%) as a white solid, which was separated bychiral prep SFC (Column Whelk-O R,R 25×3 cm, 5 μm; Mobile Phase: 85/15CO₂/MeOH; Flow: 85 mL/min) to give Enantiomer A (110 mg, 34%) andEnantiomer B (106 mg, 33%). Enantiomer A: ¹H NMR (400 MHz, CDCl₃) δ 8.55(d, J=1.7 Hz, 1H), 7.54 (s, 1H), 7.50-7.45 (m, 2H), 7.43-7.31 (m, 3H),6.98 (ddd, J=10.5, 9.0, 5.3 Hz, 1H), 6.02 (br. s., 1H), 3.82 (s, 3H),2.95-2.82 (m, J=8.4 Hz, 1H), 2.22 (d, J=11.6 Hz, 2H), 2.11-2.01 (m, 1H),2.00-1.82 (m, 1H), 1.76-1.62 (m, 1H), 1.51 (d, J=12.7 Hz, 1H), 1.27 (br.s., 1H), 0.91-0.84 (m, 1H). LCMS: RT=1.09 min; (ES): m/z (M+H)⁺=529.2;(Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad)2-98% B. Flow Rate=0.8 mL/min. Solvent A: H₂O−0.1% TFA. Solvent B:Acetonitrile−0.1% TFA). HPLC: RT=3.468 min; (Chromolith ODS S5 4.6×50 mm(4 min grad) 0-100% B. Flow Rate=4 mL/min. Inj. Vol.=10 uL.Wavelength=220. Oven Temp.=40° C. Solvent A: 10% MeOH−90% H₂O−0.1% TFA.Solvent B: 90% MeOH−10% H₂O−0.1% TFA). HPLC: RT=14.067 min; (Sunfire C183.5 μm, 3.0×150 mm: 95/5 to 5/95 H₂O/CH₃CN/0.05% TFA, flow=5 mL/min,gradient=15 min, at 220 nm). Chiral SFC RT=12.219 min (Column: Whelk-OR,R, 250×21 mm, 5 μm; Mobile Phase: 80/20 CO₂/methanol; Flow: 2 mL/min).Enantiomer B: Chiral SFC RT=14.392 min (Column: Whelk-O R,R, 250×21 mm,5 μm; Mobile Phase: 80/20 CO₂/Methanol; Flow: 2 mL/min).

Step 3:5-{-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-6,7,-difluoro-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazoleEnantiomer A

In a 2 dram vial was added a mixture of5-{-[(4,4-difluorocyclohexyl)(phenyl)methyl]-6,7,9-trifluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazoleEnantiomer A (20.0 mg, 0.0380 mmol) and sodium methanesulfinate (38.0mg, 0.372 mmol) in DMSO (1 mL), and the vial was capped and heated in aheating block at 90° C. overnight. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 20-100% B over 20 min, then a5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to give5-{-[(4,4-difluorocyclohexyl)(phenyl)methyl]-6,7,-difluoro-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazoleEnantiomer A. (6.80 mg, 30%). ¹H NMR (500 MHz, DMSO-d6) δ 8.75 (br. s.,1H), 8.31 (br. s., 1H), 7.67 (br. s., 2H), 7.51 (br. s., 1H), 7.41-7.26(m, 3H), 5.97 (br. s., 1H), 3.93 (br. s., 3H), 3.56 (br. s., 3H),2.14-1.89 (m, 5H), 1.87-1.67 (m, 1H), 1.48-1.26 (m, 3H). LCMS: RT=1.93min; (ES): m/z (M+H)⁺=589.1; (Column: Waters Acquity UPLC BEH C18,2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% Bover 3 min, then a 0.75-min hold at 100% B; Flow: 1.11 mL/min).

Examples 165 and 1662-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine

Step 1:7-(2-Azidopropan-2-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A mixture of2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(600 mg, 0.847 mmol) and TMS-N3 (0.281 mL, 2.12 mmol) in DCM (20 mL) wascooled to 0° C. and treated with BF₃.OEt₂ (0.537 mL, 4.24 mmol) dropwise over the period of 2 min. The mixture was slowly brought to roomtemperature over the period of 2 h and then stirred at room temperatureovernight. The mixture was quenched with 25 mL of water followed by 25mL of 10% NaHCO₃ solution and extracted with DCM (50 mL×2). The organicswere dried over Na₂SO₄, filtered, and concentrated, and the residue waspurified using silica gel column chromatography to give7-(2-azidopropan-2-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(430 mg, 0.826 mmol, 84%) as a white solid. LCMS: HPLC: RT=1.10 min; MS(ES): m/z=521 [M+1]⁺ (ACN/H₂O with NH₄OAc, Acquity BEH C18 1.7 μm(50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 2:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine

A stirred suspension of7-(2-azidopropan-2-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(0.400 g, 0.768 mmol), MeOH (10 mL), and Pd/C (10% on Carbon, 0.0400 g,0.376 mmol) was hydrogenated at room temperature under a balloon ofhydrogen gas for 3 h. The mixture was filtered through Celite and washedwith methanol (50 mL), and the filtrate was concentrated to give racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine(0.300 g, 0.607 mmol, 86%) as a white solid, which was separated bychiral prep SFC (Column: Chiral OD-H 25×2.1 cm, 5 μm; Mobile Phase:70/30 CO₂/(0.25% DEA in MeOH); Flow: 75 mL/min) to give Enantiomer A andEnantiomer B. Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.43 (d, J=1.5 Hz,1H), 8.34-8.29 (m, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.64 (d, J=7.5 Hz,2H), 7.54 (dd, J=1.5, 8.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.30-7.22 (m, 1H),5.82 (d, J=10.5 Hz, 1H), 4.03-3.96 (m, 4H), 3.82 (dd, J=3.0, 11.5 Hz,1H), 3.66-3.57 (m, 1H), 3.45-3.35 (m, 2H), 2.33-2.29 (m, 3H), 1.98 (d,J=13.6 Hz, 1H), 1.69-1.62 (m, 7H), 1.45 (dd, J=4.0, 13.1 Hz, 1H), 1.07(d, J=12.0 Hz, 1H). LCMS: HPLC: RT=1.73 min MS (ES): m/z=495.5 [M+H]⁺(ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7 μm (5×2.1) mm,gradient=4 min, wavelength=220 nm). HPLC RT=5.81 min (Column: SunfireC18 3.5 μm, 4.6×150 mm; Mobile Phase A: 5:95 acetonitrile:water with0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient 10-100% B over 15 min; Flow: 1 mL/min; Detection: UV at 220nm). Chiral SFC RT=2.41 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 70/30 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). EnantiomerB: Chiral SFC RT=3.65 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm;Mobile Phase: 70/30 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Examples 167 & 168N-{2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}-2-(dimethylamino)acetamide

A solution of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine(50.0 mg, 0.101 mmol) in DMF (1 mL) was treated with2-(dimethylamino)acetic acid (13.6 mg, 0.131 mmol), Et₃N (0.0420 mL,0.303 mmol), and HATU (50.0 mg, 0.131 mmol), and the reaction mixturewas stirred at room temperature for 16 h. The mixture was quenched with10 mL of water and extracted with EtOAc (25 mL×2), dried over Na₂SO₄,filtered, and concentrated and the residue purified by prep HPLC(Column: X bridge C18 (250×19,5μ), Mobile phase A=Buffer:10 mm AmmoniumAcetate in H₂O, Mobile phase B=ACN, Flow: 17 mL/min, Grad:T % B:0/30,10/60) to give racemicN-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}-2-(dimethylamino)acetamide(35.0 mg, 0.0590 mmol, 49%) as a white color solid, which was separatedby chiral prep SFC (Column: Chiral OD-H 250×4.6 mm, 5 μm; Mobile Phase:60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min) to give Enantiomer A andEnantiomer B. Enantiomer A: ¹H NMR (400 MHz, CD₃OD): δ 8.44 (d, J=1.60Hz, 1H), 8.30 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.58-7.60 (m, 2H),7.45 (dd, J=8.40, Hz, 1H), 7.33-7.37 (m, 2H), 7.25-7.29 (m, 1H), 5.77(d, J=10.80 Hz, 1H), 3.90-4.00 (m, 1H), 3.90 (s, 3H), 3.81 (dd, J=8.40,Hz, 1H), 3.58-3.61 (m, 1H), 3.39-3.40 (m, 2H), 3.00 (s, 2H), 2.37 (s,6H), 2.30 (s, 3H), 1.89-1.98 (m, 1H), 1.67-1.82 (m, 6H), 1.58-1.67 (m,1H), 1.41-1.44 (m, 1H), 1.09 (d, J=12.00 Hz, 1H). LCMS: RT=1.98 min, MS(ES): m/z=580.4 [M+H]⁺ (ACN/H₂O with HCOONH₄, Ascentis Express C18 2.7μm (50×2.1) mm, gradient=4 min, wavelength=220 nm); HPLC RT=5.96 min(Sunfire C18 (4.6×150) mm, 3.5 micron, Mobile Phase A:0.05% TFA inwater:Acetonitrile (95:5), Mobile Phase B:Acetonitrile:0.05% TFA inwater (95:5), FLOW: 1 mL/min, wavelength=220 nm); Chiral SFC RT=2.31(Chiral OD-H 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA inMeOH); Flow: 4 mL/min). Enantiomer B: Chiral SFC RT=4.86 (Chiral OD-H250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4mL/min).

Examples 169 and 1704-[7-(2-Hydroxypropan-2-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-3,5-dimethyl-2,3-dihydro-1,3-thiazol-2-one

Step 1: Methyl3-(5-formyl-3-methyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(489 mg, 0.929 mmol),4-chloro-3-methyl-2-oxo-2,3-dihydrothiazole-5-carbaldehyde (150 mg,0.845 mmol), and tripotassium phosphate (2M in water, 1.27 ml, 2.53mmol) in THF (10 mL) was purged under a stream of argon for 5 min.PdCl₂(dppf)-CH₂Cl₂ adduct (69.0 mg, 0.0850 mmol) was added, and the vialwas capped with a septum, evacuated, purged with argon 3 times, and thenheated to 80° C. for 2 h in a microwave. The reaction was quenched withwater (50 mL) and extracted with EtOAc (75 mL×2), dried over Na₂SO₄,concentrated, and the residue was purified using silica gel columnchromatography (ISCO 40 g flash column, 0-2% MeOH/CHCl₃ over 45 min) togive methyl3-(5-formyl-3-methyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate.LCMS: RT=1.17 min MS (ES): m/z=542 [M+1]⁺ (ACN/H₂O with NH₄OAc, AcquityBEH C18 1.7 μm (50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 2: Methyl3-(5-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A stirred solution of methyl3-(5-formyl-3-methyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(200 mg, 0.369 mmol) in MeOH (10 mL) was treated with NaBH₄ (18.2 mg,0.480 mmol) and stirred at room temperature for 45 min. The mixture wasquenched with sat.aq. NH₄Cl (30 mL) and extracted with DCM (50 mL×2),dried over Na₂SO₄, filtered, and concentrated to give methyl3-(5-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(180 mg, 0.331 mmol, 90%) as a yellow solid. LCMS: HPLC: RT=1.03 min; MS(ES): m/z=544 [M+1]⁺ (ACN/H₂O with NH₄OAc, Acquity BEH C18 1.7 μm(50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 3: Methyl3-(3,5-dimethyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a stirred solution of methyl3-(5-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(100 mg, 0.184 mmol) in DCM (10 mL) under N₂ (g) was addedtriethylsilane (0.147 ml, 0.920 mmol) followed by TFA (10.0 mL, 130mmol), and the reaction was heated to reflux for 16 h. The solvents wereremoved under vacuum, the residue was quenched with ice water, basifiedwith aq.NaHCO₃ (15 mL), and extracted with DCM (30 mL×2). The extractwas dried over Na₂SO₄, filtered, concentrated, and the residue waspurified using silica gel column chromatography (ISCO Silica gel 12 gflash column, 0-2% MeOH/CHCl₃ over 45 min) to give methyl3-(3,5-dimethyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(90.0 mg, 0.171 mmol, 93%) as a yellow solid. LCMS: HPLC: RT=1.15 min;MS (ES): m/z=528 [M+1]⁺ (ACN/H₂O with NH₄OAc, Acquity BEH C18 1.7 μm(50×2.1) mm, gradient=3 min, wavelength=220 nm).

Step 4:4-[7-(2-Hydroxypropan-2-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-3,5-dimethyl-2,3-dihydro-1,3-thiazol-2-one

A stirred solution of methyl3-(3,5-dimethyl-2-oxo-2,3-dihydrothiazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(100 mg, 0.191 mmol) in tetrahydrofuran (0.7 mL) was cooled to −20° C.and treated with methylmagnesium bromide (3M in THF, 0.316 mL, 0.948mmol). The reaction mixture was slowly allowed to warm to roomtemperature over the period of 5 h. The reaction was quenched with sat.aq. NH₄Cl (30 mL) and extracted with EtOAc (50 mL×2), dried over Na₂SO₄,filtered, and concentrated. The crude product was purified by prep. HPLC(Column: phenyl X bridge(250×19.5μ),M. Phase A: 10 mm ammonium acetatein water, M. Phase B: ACN, Flow: 17 mL/min, isocratic 0/30,10/60) togive racemic4-[7-(2-hydroxypropan-2-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-3,5-dimethyl-2,3-dihydro-1,3-thiazol-2-one(45.0 mg, 0.0840 mmol, 37%) as a white solid, which was separated byprep chiral SFC (Column: Chiral OD-H 250×30 mm, 5 μm; Mobile Phase:60/40 CO₂/(0.25% DEA in MeOH); Flow: 80 mL/min) to give Enantiomer A(18.0 mg, 0.0330 mmol, 17%) and Enantiomer B (17.0 mg, 0.0320 mmol,16%). Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J=1.5 Hz, 1H),8.29 (d, J=8.5 Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.62 (d, J=7.5 Hz,2H), 7.48 (dd, J=1.3, 8.3 Hz, 1H), 7.38-7.31 (m, 2H), 7.29-7.23 (m, 1H),5.74 (d, J=11.0 Hz, 1H), 4.00 (d, J=11.5 Hz, 1H), 3.83 (d, J=8.0 Hz,1H), 3.66-3.57 (m, 1H), 3.50-3.38 (m, 2H), 3.06 (s, 3H), 2.09-2.04 (m,3H), 1.95 (d, J=10.0 Hz, 1H), 1.70-1.60 (m, 7H), 1.47-1.40 (m, 1H), 1.13(d, J=13.1 Hz, 1H). LCMS: RT=2.00 min MS (ES): m/z=528 [M+H]⁺ (ACN/H₂Owith HCOONH₄, Ascentis Express C18 2.7 μm (50×2.1) mm, gradient=4 min,wavelength=220 nm). HPLC-RT=8.67 min Sunfire C18 (4.6×150) mm, 3.5micron, Mobile Phase A:0.05% TFA in water:Acetonitrile (95:5), MobilePhase B:Acetonitrile: 0.05% TFA in water (95:5), Flow: 1 mL/min,wavelength=220 nm). Chiral SFC RT=2.92 (Chiral OD-H 250×4.6 mm, 5 μm;Mobile Phase: 60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min). EnantiomerB: Chiral SFC RT=10.04 (Chiral OD-H 250×4.6 mm, 5 μm; Mobile Phase:60/40 CO₂/(0.25% DEA in MeOH); Flow: 4 mL/min).

Example 1714-{7-Methanesulfonyl-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Following procedures analogous to those described in (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate,the intermediate4-(7-(methylsulfonyl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethyl-1,2-oxazole(30.0 mg, 0.0880 mmol) was converted to the title compound (18.5 mg,37%). ¹H NMR (500 MHz, CDCl₃) δ 8.57 (d, J=8.2 Hz, 1H), 8.53 (d, J=1.7Hz, 1H), 8.33 (s, 1H), 7.90 (dd, J=8.2, 1.3 Hz, 1H), 7.66 (d, J=1.5 Hz,1H), 7.45 (d, J=7.5 Hz, 2H), 7.40-7.34 (m, 2H), 7.34-7.29 (m, 1H), 5.58(d, J=10.5 Hz, 1H), 4.07 (dd, J=11.7, 2.8 Hz, 1H), 3.87 (dd, J=11.7, 2.7Hz, 1H), 3.55 (td, J=11.9, 1.8 Hz, 1H), 3.36 (td, J=11.9, 1.8 Hz, 1H),3.19 (s, 3H), 3.17-3.04 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.03 (d,J=13.7 Hz, 1H), 1.67-1.59 (m, 1H), 1.45-1.34 (m, 1H), 1.07 (d, J=13.1Hz, 1H); LCMS (M+H)⁺=516; HPLC RT=2.593 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Example 1724-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

The enantiomers of (4-fluorophenyl)(oxan-4-yl)methanol (1.10 g, 5.23mmol) were separated on preparative SFC. (Column: Chiralpak AD-H 5×25cm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 150 mL/min; Temperature40° C.). The fractions containing the separated peaks were concentratedand dried under vacuum to give white solids. Enantiomer A:(S)-(4-fluorophenyl)(oxan-4-yl)methanol (496 mg, 45%) SFC RT=2.30 min(Column: Chiralpac AD 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH;Flow: 3 mL/min); Temperature 35° C. Enantiomer B:(R)-(4-fluorophenyl)(oxan-4-yl)methanol (530 mg, 48%) SFC RT=3.17 min(Column: Chiralpac AD 250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH;Flow: 3 mL/min); Temperature 35° C.

Following procedures analogous to those described in4-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole,the intermediate4-(7-(methylsulfonyl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethyl-1,2-oxazole(30.0 mg, 0.0880 mmol) and (R)-(4-fluorophenyl)(oxan-4-yl)methanol (37mg, 0.176 mmol) were converted to the title compound (13.9 mg, 29%). ¹HNMR (500 MHz, CDCl₃) δ 8.57 (d, J=8.2 Hz, 1H), 8.54 (d, J=1.7 Hz, 1H),8.30 (s, 1H), 7.91 (dd, J=8.2, 1.3 Hz, 1H), 7.63 (s, 1H), 7.44 (dd,J=8.6, 5.1 Hz, 2H), 7.10-7.02 (m, 2H), 5.55 (d, J=10.7 Hz, 1H), 4.08(dd, J=11.6, 2.7 Hz, 1H), 3.87 (dd, J=11.8, 2.7 Hz, 1H), 3.55 (td,J=11.9, 1.8 Hz, 1H), 3.39-3.30 (m, 1H), 3.20 (s, 3H), 3.12-3.02 (m, 1H),2.44 (s, 3H), 2.28 (s, 3H), 1.99 (d, J=13.6 Hz, 1H), 1.67-1.59 (m, 1H),1.45-1.34 (m, 1H), 1.08 (d, J=13.1 Hz, 1H); LCMS (M+H)⁺=534.4; HPLCRT=2.645 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Examples 173-174

The compounds in Table 6 were prepared according to the proceduredescribed for4-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole:

TABLE 6 HPLC RT LCMS HPLC Example X Y (min) (M + H) Method 173Enantiomer

8.69 534.4 A 174 Enantiomer

10.64 534.4 A N/A: Not Applicable/Available

-   -   HPLC Conditions for Table 6: Method A: Column: Chiral IB,        250×4.6 mm, 5 μm particles; Mobile Phase: 80/20 CO₂/MeOH; Flow:        2 mL/min; Detection UV at 220 nm.

Example 1752-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]propan-2-ol

Step 1: Methyl4-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Following procedures analogous to those described for methyl3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate,2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine (200 mg, 0.894mmol) and 4-(methoxycarbonyl)phenyl)boronic acid (322 mg, 1.79 mmol)were converted to the title compound (122 mg, 38%). LCMS (M+H)=358.2;HPLC RT=2.268 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A:10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2: Methyl4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following procedures analogous to those described for methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,methyl4-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate(121 mg, 0.340 mmol) was converted to the title compound (96.0 mg, 88%).¹H NMR (400 MHz, CDCl₃) δ 9.24-9.08 (m, 1H), 8.61 (s, 1H), 8.58 (d,J=1.8 Hz, 1H), 8.32 (dd, J=8.6, 1.7 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H),7.57 (d, J=8.6 Hz, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 2.40 (s, 3H); LCMS(M+H)=322.3; HPLC RT=1.895 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 3: (S)-Methyl4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following procedures analogous to those described for (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate,methyl4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(30.0 mg, 0.0930 mmol) was converted to the title compound (19.6 mg,42%). LCMS (M+H)=496; HPLC RT=2.836 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Step 4:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]propan-2-ol

Following procedures analogous to those described for(S)-2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,(S)-methyl4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(19.6 mg, 0.0400 mmol) was converted to the title compound (19.6 mg,100%). ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d, J=1.5 Hz, 1H), 8.45 (d, J=1.7Hz, 1H), 7.90 (dd, J=8.7, 2.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.59 (d,J=1.8 Hz, 1H), 7.45 (d, J=7.2 Hz, 2H), 7.38-7.32 (m, 2H), 7.31-7.28 (m,1H), 5.50 (d, J=10.7 Hz, 1H), 4.06 (dd, J=11.8, 2.8 Hz, 1H), 3.94-3.84(m, 4H), 3.54 (td, J=11.9, 2.0 Hz, 1H), 3.36 (td, J=11.9, 2.0 Hz, 1H),3.10 (qt, J=11.1, 3.5 Hz, 1H), 2.31 (s, 3H), 2.01 (d, J=13.4 Hz, 1H),1.87 (s, 1H), 1.75 (d, J=1.5 Hz, 6H), 1.65-1.59 (m, 1H), 1.47-1.36 (m,1H), 1.19-1.11 (m, 1H); LCMS (M+H)=496.4; HPLC RT=2.535 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Example 1762-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-8-yl]propan-2-ol

Step 1: (S)-Methyl4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(4-fluorophenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following procedures analogous to those described for (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate,methyl4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(30.0 mg, 0.0930 mmol) and (R)-(4-fluorophenyl)(oxan-4-yl)methanol (36.6mg, 0.174 mmol) were converted to the title compound (19.6 mg, 42%).LCMS (M+H)=496; HPLC RT=2.836 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 2:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-8-yl]propan-2-ol

Following procedures analogous to those described2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]propan-2-ol,(S)-methyl4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-fluorophenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(15.3 mg, 0.0300 mmol) was converted to the title compound (14.8 mg,95%). ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d, J=1.4 Hz, 1H), 8.47 (d, J=1.7Hz, 1H), 7.89 (dd, J=8.7, 2.0 Hz, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.58 (d,J=1.5 Hz, 1H), 7.46-7.39 (m, 2H), 7.07-7.01 (m, 2H), 5.46 (d, J=10.7 Hz,1H), 4.06 (dd, J=11.6, 2.6 Hz, 1H), 3.95 (s, 3H), 3.87 (dd, J=11.7, 2.9Hz, 1H), 3.54 (td, J=11.9, 2.1 Hz, 1H), 3.36 (td, J=11.9, 2.0 Hz, 1H),3.11-3.01 (m, 1H), 2.33 (s, 3H), 1.96 (d, J=13.0 Hz, 1H), 1.86 (s, 1H),1.74 (s, 6H), 1.65-1.59 (m, 1H), 1.45-1.36 (m, 1H), 1.20-1.13 (m, 1H);LCMS (M+H)=514.4; HPLC RT=2.577 min (Column: Chromolith ODS S5 4.6×50mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B:90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% Bover 4 min; Flow: 4 mL/min).

Example 1775-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Step 1:2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazole)-N-(3-(methylsulfonyl)phenyl)pyridin-3-amine

Following procedures analogous to those described for methyl3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate,2-chloro-5-(dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine (500 mg, 2.24mmol) and (3-(methylsulfonyl)phenyl)boronic acid (939 mg, 4.69 mmol)were converted to the title compound (287 mg, 34%). LCMS (M+H)=378.2;HPLC RT=1.700 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A:10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2:5-(7-(Methylsulfonyl)-5H-pyrido[3,2-b]indol-3-yl)-1,4-dimethyl-1H-1,2,3-triazole

Following procedures analogous to those described for methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazole)-N-(3-(methylsulfonyl)phenyl)pyridin-3-amine(287 mg, 0.760 mmol) was converted to the title compound (111 mg, 43%).¹H NMR (500 MHz, CDCl₃) δ 8.83 (s, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.60 (d,J=8.2 Hz, 1H), 8.22 (d, J=0.9 Hz, 1H), 7.94 (dd, J=8.2, 1.5 Hz, 1H),7.82 (d, J=1.8 Hz, 1H), 4.06 (s, 3H), 3.19 (s, 3H), 2.41 (s, 3H); LCMS(M+H)=322.3; HPLC RT=1.512 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 3:5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following procedures analogous to those described for4-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole,5-(7-(methylsulfonyl)-5H-pyrido[3,2-b]indol-3-yl)-1,4-dimethyl-1H-1,2,3-triazole(30.0 mg, 0.0880 mmol) was converted to the title compound (18.8 mg,41%). ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J=8.2 Hz, 1H), 8.57 (d, J=1.7Hz, 1H), 8.37 (s, 1H), 7.93 (dd, J=8.2, 1.3 Hz, 1H), 7.70 (d, J=1.5 Hz,1H), 7.47-7.42 (m, 2H), 7.41-7.35 (m, 2H), 7.35-7.31 (m, 1H), 5.61 (d,J=10.5 Hz, 1H), 4.07 (dd, J=11.6, 2.9 Hz, 1H), 3.91 (s, 3H), 3.88 (dd,J=11.8, 2.8 Hz, 1H), 3.56 (td, J=12.0, 1.8 Hz, 1H), 3.36 (td, J=11.9,1.8 Hz, 1H), 3.21 (s, 3H), 3.16-3.06 (m, 1H), 2.34-2.29 (m, 3H), 2.04(d, J=14.5 Hz, 1H), 1.68-1.60 (m, 1H), 1.47-1.36 (m, 1H), 1.07 (d,J=13.0 Hz, 1H); LCMS (M+H)=516.4; HPLC RT=2.362 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Example 1785-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,5-(7-(methylsulfonyl)-5H-pyrido[3,2-b]indol-3-yl)-1,4-dimethyl-1H-1,2,3-triazole(30.0 mg, 0.0880 mmol) was converted to the title compound (16.4 mg,34%). ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d, J=8.2 Hz, 1H), 8.58 (d, J=1.7Hz, 1H), 8.34 (s, 1H), 7.94 (dd, J=8.2, 1.2 Hz, 1H), 7.69 (s, 1H), 7.43(dd, J=8.5, 5.0 Hz, 2H), 7.07 (t, J=8.5 Hz, 2H), 5.57 (d, J=10.7 Hz,1H), 4.08 (dd, J=11.7, 2.9 Hz, 1H), 3.96 (s, 3H), 3.88 (dd, J=11.7, 2.7Hz, 1H), 3.55 (td, J=11.9, 1.7 Hz, 1H), 3.39-3.32 (m, 1H), 3.21 (s, 3H),3.12-3.02 (m, 1H), 2.33 (s, 3H), 1.99 (d, J=13.3 Hz, 1H), 1.67-1.60 (m,1H), 1.40 (qd, J=12.3, 4.5 Hz, 1H), 1.08 (d, J=13.0 Hz, 1H); LCMS(M+H)=534.4; HPLC RT=2.408 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 179(5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1-methyl-1H-1,2,3-triazol-4-yl)methanol

Step 1: 5-Bromo-2-(4-methanesulfonylphenyl)-3-nitropyridine

Following procedures analogous to those described for methyl4-(5-bromo-3-nitropyridin-2-yl)benzoate,(3-(methylsulfonyl)phenyl)boronic acid (114 mg, 0.568 mmol) wasconverted to the title compound (185 mg, 91%). LCMS (M+H)=357; HPLCRT=1.798 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2: 3-Bromo-7-methanesulfonyl-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate,5-bromo-2-(4-methanesulfonylphenyl)-3-nitropyridine (185 mg, 0.520 mmol)was converted to the title compound (74.8 mg, 44%). ¹H NMR (500 MHz,CDCl₃) δ 8.71 (d, J=2.0 Hz, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.48 (br. s.,1H), 8.16-8.13 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.90 (dd, J=8.2, 1.5 Hz,1H), 3.16 (s, 3H); LCMS (M+H)=325; HPLC RT=1.945 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Step 3:3-Bromo-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-7-methanesulfonyl-5H-pyrido[3,2-b]indole (74.0 mg, 0.230 mmol)was converted to the title compound (57.0 mg, 50%). ¹H NMR (500 MHz,CDCl₃) δ 8.66 (d, J=1.8 Hz, 1H), 8.51 (d, J=8.1 Hz, 1H), 8.26 (d, J=0.8Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.86 (dd, J=8.2, 1.4 Hz, 1H), 7.50-7.44(m, 2H), 7.42-7.35 (m, 2H), 7.34-7.29 (m, 1H), 5.45 (d, J=11.0 Hz, 1H),4.07 (dd, J=11.8, 3.0 Hz, 1H), 3.87 (dd, J=11.8, 3.0 Hz, 1H), 3.56 (td,J=11.9, 2.1 Hz, 1H), 3.38 (td, J=11.9, 2.1 Hz, 1H), 3.19-3.07 (m, 4H),1.98 (d, J=13.1 Hz, 1H), 1.65-1.57 (m, 1H), 1.43-1.32 (m, 1H), 1.03 (dd,J=13.4, 1.3 Hz, 1H); LCMS (M+H)=499; HPLC RT=2.828 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 4:(5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1-methyl-1H-1,2,3-triazol-4-yl)methanol

Following procedures analogous to those described for methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,3-bromo-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole(57.0 mg, 0.114 mmol) and4-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(tributylstannyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole(101 mg, 0.171 mmol) were converted, after desilylation with 1M TBAF inTHF (1.70 mL, 1.70 mmol), to the title compound (61.0 mg, 99%). ¹H NMR(500 MHz, CDCl₃) δ 8.68 (d, J=1.7 Hz, 1H), 8.60 (d, J=8.2 Hz, 1H), 8.39(s, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.92 (dd, J=8.2, 1.4 Hz, 1H), 7.56-7.50(m, 2H), 7.40-7.35 (m, 2H), 7.34-7.29 (m, 1H), 5.58 (d, J=10.8 Hz, 1H),4.80-4.74 (m, 1H), 4.72-4.66 (m, 1H), 4.09 (s, 3H), 4.06 (dd, J=11.8,2.8 Hz, 1H), 3.87 (dd, J=11.7, 2.9 Hz, 1H), 3.55 (td, J=11.9, 1.9 Hz,1H), 3.41 (td, J=11.9, 2.0 Hz, 1H), 3.30-3.22 (m, 1H), 3.21 (s, 3H),2.36 (t, J=6.3 Hz, 1H), 1.97 (d, J=13.4 Hz, 1H), 1.64-1.59 (m, 1H),1.46-1.36 (m, 1H), 1.10 (d, J=12.5 Hz, 1H); LCMS (M+H)=532; HPLCRT=2.107 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Example 1804-(Fluoromethyl)-5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1-methyl-1H-1,2,3-triazole

In a 20 mL flask containing(5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1-methyl-1H-1,2,3-triazol-4-yl)methanol(47.0 mg, 0.0880 mmol) cooled in a −78° C. bath was added DAST (53.0 uL,0.398 mmol). The reaction mixture was stirred for 1 h in the −78° C.bath then sat. aq. NaHCO₃ was added, and the reaction was allowed towarm to room temperature. The reaction mixture was then diluted with 10%aq. LiCl and extracted twice with CHCl₃. The combined organic layerswere dried over MgSO₄, filtered, and concentrated. The crude residue waspurified on a silica gel column (40 g) and eluted with a gradient from100% CH₂Cl₂ to 4% MeOH/CH₂Cl₂. The tubes with product were collected andconcentrated to give the title compound (33.7 mg, 71%). ¹H NMR (400 MHz,CDCl₃) δ 8.66 (d, J=1.8 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.40 (s, 1H),8.06 (d, J=1.5 Hz, 1H), 7.94 (dd, J=8.4, 1.3 Hz, 1H), 7.48 (d, J=7.3 Hz,2H), 7.41-7.34 (m, 2H), 7.34-7.29 (m, 1H), 5.58 (d, J=10.8 Hz, 1H),5.53-5.45 (m, 1H), 5.40-5.33 (m, 1H), 4.09 (s, 3H), 4.08-4.02 (m, 1H),3.87 (dd, J=12.0, 2.8 Hz, 1H), 3.60-3.50 (m, 1H), 3.38 (td, J=11.9, 2.0Hz, 1H), 3.21 (s, 3H), 3.20-3.12 (m, 1H), 1.97 (d, J=12.8 Hz, 1H),1.65-1.57 (m, 1H), 1.47-1.35 (m, 1H), 1.09 (d, J=12.8 Hz, 1H); LCMS(M+H)=534; HPLC RT=2.375 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 1815-{9-Fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Step 1: 5-Bromo-2-(2-fluoro-5-methanesulfonylphenyl)-3-nitropyridine

Following procedures analogous to those described for methyl4-(5-bromo-3-nitropyridin-2-yl)benzoate,2-(2-fluoro-5-methanesulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(500 mg, 1.66 mmol) was converted to the title compound (325 mg, 52%).¹H NMR (500 MHz, CDCl₃) δ 9.02 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0 Hz,1H), 8.34 (dd, J=6.5, 2.4 Hz, 1H), 8.10 (ddd, J=8.7, 4.7, 2.4 Hz, 1H),7.34 (dd, J=9.4, 8.8 Hz, 1H), 3.15 (s, 3H); LCMS (M+H)=375; HPLCRT=1.977 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2: 3-Bromo-9-fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate,5-bromo-2-(2-fluoro-5-methanesulfonylphenyl)-3-nitropyridine (325 mg,0.866 mmol) was converted to the title compound (173 mg, 58%). ¹H NMR(500 MHz, DMSO-d₆) δ 11.99 (s, 1H), 8.68 (d, J=2.1 Hz, 1H), 8.30 (d,J=2.1 Hz, 1H), 8.05 (dd, J=8.5, 4.9 Hz, 1H), 7.31 (dd, J=9.8, 8.7 Hz,1H), 3.38 (s, 3H); LCMS (M+H)=343; HPLC RT=1.998 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Step 3:3-Bromo-9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-9-fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indole (100 mg, 0.290mmol) was converted to the title compound (121 mg, 81%). ¹H NMR (500MHz, CDCl₃) δ 8.71 (d, J=1.5 Hz, 1H), 8.36 (dd, J=8.8, 5.3 Hz, 1H), 7.78(d, J=1.5 Hz, 1H), 7.51 (d, J=7.6 Hz, 2H), 7.44-7.31 (m, 3H), 7.18 (t,J=8.6 Hz, 1H), 6.96 (d, J=9.8 Hz, 1H), 4.06 (d, J=8.9 Hz, 1H), 3.86-3.70(m, 1H), 3.53 (t, J=11.2 Hz, 1H), 3.34-3.15 (m, 4H), 2.92 (q, J=11.0 Hz,1H), 2.11 (d, J=13.4 Hz, 1H), 1.97-1.79 (m, 1H), 1.54-1.44 (m, 1H), 0.37(d, J=12.4 Hz, 1H); LCMS (M+H)=517; HPLC RT=2.913 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 4:5-{9-Fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following procedures analogous to those described for methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,3-bromo-9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole(60.0 mg, 0.116 mmol) was converted to the title compound (21.8 mg,33%). ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.9,5.3 Hz, 1H), 7.52 (d, J=7.9 Hz, 2H), 7.46 (d, J=1.8 Hz, 1H), 7.43-7.37(m, 2H), 7.37-7.32 (m, 1H), 7.24 (t, J=8.7 Hz, 1H), 7.00 (d, J=9.8 Hz,1H), 4.07 (dd, J=11.6, 2.6 Hz, 1H), 3.78 (dd, J=11.7, 3.1 Hz, 1H), 3.72(s, 3H), 3.57-3.50 (m, 1H), 3.37 (s, 3H), 3.21 (td, J=12.0, 2.0 Hz, 1H),3.00-2.87 (m, 1H), 2.20 (br. s., 1H), 2.18 (s, 3H), 2.03-1.93 (m, 1H),1.68-1.58 (m, 1H), 0.38 (d, J=12.7 Hz, 1H); LCMS (M+H)=534; HPLCRT=2.463 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Example 1825-{6-Methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

To an 8 mL vial containing5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole(50.0 mg, 0.0940 mmol) in DMSO (2 mL) was added NaOMe (101 mg, 1.87mmol). The reaction mixture was stirred at room temperature for 20 minthen diluted with water, cooled with ice, and neutralized with aq. 1Mcitric acid. The white precipitate that formed was collected byfiltration and purified on prep HPLC (Column: Phen Luna C18, 30×100 mm,5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 10-100%B over 12 min, then a 3-min hold at 100% B; Flow: 40 mL/min). The tubescontaining product were basified with sat aq. K₂CO₃ and concentrated toremove acetonitrile. A white precipitate formed while concentrating andwas filtered with water rinses and dried under vacuum to give the titlecompound (27.1 mg, 52%). ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, J=1.7 Hz,1H), 8.40 (d, J=8.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.42 (d, J=1.7 Hz,1H), 7.40-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.04-6.93 (m, 2H), 4.30 (s,3H), 4.06 (d, J=9.2 Hz, 1H), 3.75 (dd, J=11.3, 2.9 Hz, 1H), 3.70 (s,3H), 3.52 (t, J=11.1 Hz, 1H), 3.32 (s, 3H), 3.23-3.13 (m, 1H), 2.98-2.85(m, 1H), 2.22-2.14 (m, 4H), 2.03-1.91 (m, 1H), 1.63-1.58 (m, 1H), 0.36(d, J=12.8 Hz, 1H); LCMS (M+H)=546; HPLC RT=2.325 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Example 1835-{6-Methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Step 1: 5-Bromo-2-(5-methanesulfonyl-2-methoxyphenyl)-3-nitropyridine

Following procedures analogous to those described for methyl4-(5-bromo-3-nitropyridin-2-yl)benzoate,2-(5-methanesulfonyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.00 g, 3.20 mmol) was converted to the title compound (789 mg, 63%).¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.0 Hz, 1H), 8.43 (d, J=2.1 Hz,1H), 8.25 (d, J=2.3 Hz, 1H), 8.05 (dd, J=8.7, 2.4 Hz, 1H), 7.06 (d,J=8.8 Hz, 1H), 3.82 (s, 3H), 3.12 (s, 3H); LCMS (M+H)=387; HPLC RT=1.952min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2: 3-Bromo-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate,5-bromo-2-(5-methanesulfonyl-2-methoxyphenyl)-3-nitropyridine (788 mg,2.03 mmol) was converted to the title compound (321 mg, 44%). ¹H NMR(400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.22 (d,J=2.0 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.10 (s,3H), 3.30 (s, 3H); LCMS (M+H)=355; HPLC RT=1.635 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Step 3:3-Bromo-6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole (166 mg,0.470 mmol) was converted to the title compound (172 mg, 69%). ¹H NMR(400 MHz, CDCl₃) δ 8.70 (d, J=2.0 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 7.74(d, J=2.0 Hz, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.44-7.36 (m, 2H), 7.35-7.30(m, 1H), 6.98-6.91 (m, 2H), 4.25 (s, 3H), 4.05 (d, J=11.2 Hz, 1H), 3.74(dd, J=11.9, 2.7 Hz, 1H), 3.51 (t, J=10.9 Hz, 1H), 3.27-3.15 (m, 4H),2.98-2.83 (m, 1H), 2.10 (d, J=13.3 Hz, 1H), 1.97-1.83 (m, 1H), 1.51-1.42(m, 1H), 0.35 (d, J=12.6 Hz, 1H); LCMS (M+H)=529; HPLC RT=2.766 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 4:5-{6-Methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

In a 4 mL vial was combined3-bromo-6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole(30.0 mg, 0.0570 mmol),4-(²H₃)methyl-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole (19.5 mg,0.113 mmol), and tetrabutylammonium acetate (34.2 mg, 0.113 mmol) in NMP(0.1 mL). To the mixture was addedtris(dibenzylideneacetone)dipalladium-chloroform adduct (5.80 mg,0.00500 mmol), the vial was sealed under N₂ (g) and heated on a 100° C.heating block for 3 h. The reaction mixture was cooled to roomtemperature, and a 1M solution of TBAF in THF (0.560 mL, 0.560 mmol) wasadded. After stirring for 10 min, sat. aq. NH₄OH was added, and then themixture was concentrated to remove THF. The residue was diluted with 10%aq. LiCl, and the resulting precipitate was collected by filtration. Thecrude solid was purified on prep HPLC (Column: Phen Luna C18, 30×100 mm,5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 10-100%B over 12 min, then a 3-min hold at 100% B; Flow: 40 mL/min). The tubescontaining product were basified with sat. aq. K₂CO₃ and concentrated toremove acetonitrile. A white precipitate formed while concentrating andwas filtered with water rinses and dried under vacuum to give the titlecompound (11.7 mg, 37%). ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, J=1.8 Hz,1H), 8.41 (d, J=8.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.42 (d, J=1.8 Hz,1H), 7.40-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.02-6.95 (m, 2H), 4.30 (s,3H), 4.06 (dd, J=11.7, 2.7 Hz, 1H), 3.75 (dd, J=11.3, 3.1 Hz, 1H), 3.70(s, 3H), 3.52 (t, J=10.8 Hz, 1H), 3.32 (s, 3H), 3.18 (td, J=12.0, 1.8Hz, 1H), 2.99-2.87 (m, 1H), 2.24-2.14 (m, 1H), 2.04-1.92 (m, 1H),1.63-1.57 (m, 1H), 0.36 (d, J=13.0 Hz, 1H); LCMS (M+H)=549; HPLCRT=2.292 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Example 1845-[6-(²H₃)Methanesulfonyl-9-(²H₃)methoxy-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

In a 4 mL vial containing a solution of KOtBu (56.8 mg, 0.510 mmol) inCD₃OD (0.750 mL) was added(5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole(27.0 mg, 0.0510 mmol) to give a white suspension. The reaction mixturewas diluted with DMSO (0.4 mL) and the solid dissolved. After stirringfor 30 min at room temperature, the reaction was neutralized with 1M aq.citric acid and then concentrated. The mixture was diluted with water,and the resulting white precipitate was collected by filtration to givethe title compound (23.3 mg, 83%). ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d,J=1.8 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.42 (d,J=1.8 Hz, 1H), 7.40-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.02-6.92 (m, 2H),4.05 (dd, J=11.8, 2.7 Hz, 1H), 3.75 (dd, J=11.6, 3.1 Hz, 1H), 3.70 (s,3H), 3.55-3.47 (m, 1H), 3.22-3.13 (m, 1H), 2.98-2.86 (m, 1H), 2.24-2.13(m, 4H), 2.03-1.92 (m, 1H), 1.57-1.50 (m, 1H), 0.36 (d, J=12.8 Hz, 1H);LCMS (M+H)=552; HPLC RT=2.325 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 1854-{6-Methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Step 1:4-{9-Fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Following procedures analogous to those described for2-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-3-amine,3-bromo-9-fluoro-6-methanesulfonyl-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole(60.0 mg, 0.116 mmol) was converted to the title compound (55.0 mg,88%). ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J=1.7 Hz, 1H), 8.36 (dd, J=8.9,5.3 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.43-7.37 (m, 3H), 7.36-7.30 (m,1H), 7.21 (t, J=8.7 Hz, 1H), 6.99 (d, J=9.8 Hz, 1H), 4.06 (dd, J=11.6,2.7 Hz, 1H), 3.77 (dd, J=11.7, 3.1 Hz, 1H), 3.52 (td, J=11.9, 1.8 Hz,1H), 3.34 (s, 3H), 3.21 (td, J=12.0, 2.0 Hz, 1H), 3.01-2.87 (m, 1H),2.25 (s, 3H), 2.22-2.14 (m, 1H), 2.08 (s, 3H), 2.02-1.90 (m, 1H),1.63-1.57 (m, 1H), 0.38 (d, J=12.8 Hz, 1H); LCMS (M+H)=534; HPLCRT=2.731 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2:4-{6-Methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Following procedures analogous to those described for5-{6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,4-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole(55.0 mg, 0.100 mmol) was converted to the title compound (21.7 mg,38%). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=1.6 Hz, 1H), 8.37 (d, J=8.9Hz, 1H), 7.52 (d, J=7.6 Hz, 2H), 7.43-7.35 (m, 3H), 7.32 (d, J=7.2 Hz,1H), 7.02-6.93 (m, 2H), 4.28 (s, 3H), 4.05 (d, J=8.8 Hz, 1H), 3.80-3.68(m, 1H), 3.50 (t, J=11.2 Hz, 1H), 3.28 (s, 3H), 3.17 (t, J=10.9 Hz, 1H),2.99-2.85 (m, 1H), 2.24 (s, 3H), 2.17 (d, J=14.1 Hz, 1H), 2.07 (s, 3H),2.03-1.91 (m, 1H), 1.51 (br. s., 1H), 0.36 (d, J=12.5 Hz, 1H); LCMS(M+H)=546; HPLC RT=2.428 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 1864-{5-[(S)-(2-Fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Step 1:3-Bromo-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole (75.0 mg,0.210 mmol) and (R)-(2-fluorophenyl) (oxan-4-yl)methanol (89.0 mg, 0.422mmol) were converted to the title compound (96.3 mg, 83%). LCMS(M+H)=547; HPLC RT=2.668 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 2:4-{5-[(S)-(2-Fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Following procedures analogous to those described for4-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole,3-bromo-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole(30.0 mg, 0.0550 mmol) was converted to the title compound (21.7 mg,66%). ¹H NMR (500 MHz, CDCl₃) δ 8.56 (d, J=1.7 Hz, 1H), 8.45 (d, J=9.0Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.36-7.28 (m,2H), 7.23 (d, J=9.9 Hz, 1H), 7.01-6.94 (m, 2H), 4.27 (s, 3H), 4.11-4.04(m, 1H), 3.84 (dd, J=11.5, 3.1 Hz, 1H), 3.58-3.47 (m, 1H), 3.35 (s, 3H),3.29-3.21 (m, 1H), 3.05 (q, J=11.1 Hz, 1H), 2.27 (s, 3H), 2.15-2.04 (m,4H), 2.00-1.89 (m, 2H), 0.58 (d, J=12.7 Hz, 1H); LCMS (M+H)=564; HPLCRT=2.280 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Example 1874-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole

Following procedures analogous to those described for4-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole,3-bromo-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole(32.5 mg, 0.0590 mmol) was converted to the title compound (28.5 mg,83%). ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J=1.7 Hz, 1H), 8.32 (d, J=9.0Hz, 1H), 7.55 (dd, J=8.5, 5.1 Hz, 2H), 7.37 (d, J=1.8 Hz, 1H), 7.11-7.04(m, 2H), 6.96 (d, J=9.0 Hz, 1H), 6.92 (d, J=9.8 Hz, 1H), 4.28 (s, 3H),4.05 (d, J=9.2 Hz, 1H), 3.73 (dd, J=11.6, 2.9 Hz, 1H), 3.49 (t, J=11.1Hz, 1H), 3.31 (s, 3H), 3.20-3.11 (m, 1H), 2.93-2.82 (m, 1H), 2.29 (s,3H), 2.17-2.08 (m, 4H), 1.97-1.85 (m, 1H), 1.51-1.40 (m, 1H), 0.33 (d,J=13.4 Hz, 1H); LCMS (M+H)=564; HPLC RT=2.473 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Example 1885-{5-[(S)-(2-Fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole(30.0 mg, 0.0550 mmol) was converted to the title compound (13.5 mg,43%). ¹H NMR (500 MHz, CDCl₃) δ 8.59 (br. s., 1H), 8.50 (d, J=8.9 Hz,1H), 7.75 (t, J=7.7 Hz, 1H), 7.51 (br. s., 1H), 7.39-7.28 (m, 2H),7.03-6.87 (m, 2H), 4.28 (s, 3H), 4.12-4.02 (m, 1H), 3.85 (d, J=8.5 Hz,1H), 3.76 (br. s., 3H), 3.53 (t, J=11.1 Hz, 1H), 3.37 (s, 3H), 3.26 (t,J=11.4 Hz, 1H), 3.04 (d, J=10.7 Hz, 1H), 2.24-1.90 (m, 6H), 0.59 (d,J=13.0 Hz, 1H); LCMS (M+H)=564; HPLC RT=2.243 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Example 1895-{5-[(S)-(2-Fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,3-bromo-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole(30.0 mg, 0.0550 mmol) was converted to the title compound (6.70 mg,21%). ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J=1.8 Hz, 1H), 8.49 (d, J=8.9Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.37-7.31 (m,1H), 7.31-7.28 (m, 1H), 7.24 (s, 1H), 7.02-6.94 (m, 2H), 4.28 (s, 3H),4.10-4.06 (m, 1H), 3.85 (dd, J=11.9, 3.1 Hz, 1H), 3.76 (s, 3H),3.57-3.49 (m, 1H), 3.37 (s, 3H), 3.26 (td, J=12.0, 1.8 Hz, 1H),3.10-2.99 (m, 1H), 2.18-1.93 (m, 3H), 0.59 (d, J=12.2 Hz, 1H); LCMS(M+H)=567; HPLC RT=2.237 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 1905-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole(32.5 mg, 0.0590 mmol) was converted to the title compound (26.0 mg,77%). ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J=1.8 Hz, 1H), 8.36 (d, J=8.9Hz, 1H), 7.54 (dd, J=8.5, 5.2 Hz, 2H), 7.43 (d, J=1.8 Hz, 1H), 7.12-7.04(m, 2H), 6.99 (d, J=9.0 Hz, 1H), 6.94 (d, J=9.9 Hz, 1H), 4.29 (s, 3H),4.05 (dd, J=11.5, 2.8 Hz, 1H), 3.80 (s, 3H), 3.75 (dd, J=11.7, 3.1 Hz,1H), 3.54-3.46 (m, 1H), 3.34 (s, 3H), 3.16 (td, J=11.9, 1.8 Hz, 1H),2.94-2.82 (m, 1H), 2.20 (s, 3H), 2.12 (d, J=13.6 Hz, 1H), 1.99-1.86 (m,1H), 1.53-1.45 (m, 1H), 0.34 (d, J=12.5 Hz, 1H); LCMS (M+H)=564; HPLCRT=2.405 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Example 1915-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,3-bromo-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indole(28.5 mg, 0.0520 mmol) was converted to the title compound (2.80 mg,9.4%). ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J=1.8 Hz, 1H), 8.36 (d, J=8.9Hz, 1H), 7.54 (dd, J=8.3, 5.1 Hz, 2H), 7.43 (d, J=1.8 Hz, 1H), 7.10-7.05(m, 2H), 6.99 (d, J=9.0 Hz, 1H), 6.94 (d, J=9.5 Hz, 1H), 4.29 (s, 3H),4.05 (d, J=9.2 Hz, 1H), 3.80 (s, 3H), 3.75 (d, J=12.1 Hz, 1H), 3.50 (t,J=11.0 Hz, 1H), 3.34 (s, 3H), 3.21-3.11 (m, 1H), 2.95-2.82 (m, 1H), 2.12(d, J=13.1 Hz, 1H), 1.98-1.86 (m, 1H), 1.50 (d, J=4.6 Hz, 1H), 0.34 (d,J=12.7 Hz, 1H); LCMS (M+H)=567; HPLC RT=2.392 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Example 1922-{3-[5-(²H₃)Methyl-3-methyl-1,2-oxazol-4-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

In a 4 mL vial containing2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(20.0 mg, 0.0400 mmol) in CD₃OD (1.5 mL) was added KOtBu (20.4 mg, 0.182mmol). The mixture was heated on an 80° C. heating block for 23 h, thenat room temperature sat. aq. NaHCO₃ was added, and the mixture wasconcentrated to remove CD₃OD. The mixture was diluted with water, andthe resulting white precipitate was collected by filtration to give thetitle compound (18.1 mg, 89%). ¹H NMR (500 MHz, CDCl₃) δ 8.39 (d, J=1.7Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.94 (s, 1H), 7.52 (d, J=1.7 Hz, 1H),7.46 (d, J=7.3 Hz, 2H), 7.42 (dd, J=8.2, 1.4 Hz, 1H), 7.37-7.31 (m, 2H),7.30-7.28 (m, 1H), 5.56 (d, J=10.7 Hz, 1H), 4.06 (dd, J=11.7, 2.6 Hz,1H), 3.86 (dd, J=11.7, 2.8 Hz, 1H), 3.55 (td, J=11.9, 1.8 Hz, 1H), 3.35(td, J=11.9, 2.0 Hz, 1H), 3.16-3.04 (m, 1H), 2.23 (s, 3H), 2.03 (d,J=13.4 Hz, 1H), 1.93 (s, 1H), 1.74 (s, 6H), 1.68-1.59 (m, 1H), 1.47-1.36(m, 1H), 1.11 (d, J=13.6 Hz, 1H); LCMS (M+H)=499; HPLC RT=2.422 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Example 1934-[6-(²H₃)Methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-5-(²H₃)methyl-3-methyl-1,2-oxazole

Following procedures analogous to those described for2-{3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,4-{6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3,5-dimethyl-1,2-oxazole(11.0 mg, 0.0200 mmol) was converted to the title compound (9.00 mg,80%). ¹H NMR (500 MHz, CDCl₃) δ 8.59 (d, J=1.8 Hz, 1H), 8.36 (d, J=8.9Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.41-7.35 (m, 3H), 7.34-7.29 (m, 1H),6.99-6.93 (m, 2H), 4.28 (s, 3H), 4.05 (dd, J=11.5, 2.7 Hz, 1H), 3.74(dd, J=11.6, 3.2 Hz, 1H), 3.51 (td, J=11.9, 1.8 Hz, 1H), 3.18 (td,J=11.9, 1.9 Hz, 1H), 3.00-2.87 (m, 1H), 2.17 (d, J=13.7 Hz, 1H), 2.07(s, 3H), 2.03-1.92 (m, 1H), 1.53 (dd, J=12.8, 4.4 Hz, 1H), 0.35 (d,J=13.0 Hz, 1H); LCMS (M+H)=552; HPLC RT=2.392 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min).

Example 1945-{9-Fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Step 1: 5-Bromo-2-(2-fluoro-4-methanesulfonylphenyl)-3-nitropyridine

Following procedures analogous to those described for methyl4-(5-bromo-3-nitropyridin-2-yl)benzoate,2-(2-fluoro-4-methanesulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.96 g, 9.86 mmol) was converted to the title compound (469 mg, 13%).¹H NMR (400 MHz, CDCl₃) δ 9.03 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.1 Hz,1H), 8.02-7.86 (m, 2H), 7.73 (dd, J=9.2, 1.5 Hz, 1H), 3.14 (s, 3H); HPLCRT=1.973 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2: 3-Bromo-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate,5-bromo-2-(2-fluoro-4-methanesulfonylphenyl)-3-nitropyridine (469 mg,1.25 mmol) was converted to the title compound (136 mg, 32%). ¹H NMR(500 MHz, DMSO-d₆) δ 12.34 (br. s., 1H), 8.69 (br. s., 1H), 8.39 (s,1H), 8.01 (s, 1H), 7.60 (d, J=9.5 Hz, 1H), 3.34 (br. s., 3H); LCMS(M+H)=343; HPLC RT=1.940 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 3:3-Bromo-9-fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indole (136 mg, 0.400mmol) was converted to the title compound (76.0 mg, 37%). ¹H NMR (500MHz, CDCl₃) δ 8.75 (d, J=1.8 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 8.06 (s,1H), 7.54 (dd, J=8.9, 0.9 Hz, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.41-7.36 (m,2H), 7.35-7.31 (m, 1H), 5.46 (d, J=11.0 Hz, 1H), 4.07 (dd, J=11.7, 2.9Hz, 1H), 3.88 (dd, J=11.8, 3.0 Hz, 1H), 3.57 (td, J=11.9, 2.0 Hz, 1H),3.38 (td, J=11.9, 2.1 Hz, 1H), 3.15-3.05 (m, 4H), 2.00 (d, J=13.3 Hz,1H), 1.64-1.57 (m, 1H), 1.42-1.32 (m, 1H), 1.00 (d, J=12.2 Hz, 1H); LCMS(M+H)=517; HPLC RT=2.761 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 4:5-{9-Fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following procedures analogous to those described for methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,3-bromo-9-fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole(38.0 mg, 0.0730 mmol) was converted to the title compound (28.2 mg,71%). ¹H NMR (500 MHz, CDCl₃) δ 8.66 (d, J=1.7 Hz, 1H), 8.18 (s, 1H),7.71 (d, J=1.5 Hz, 1H), 7.64-7.59 (m, 1H), 7.46-7.42 (m, 2H), 7.41-7.37(m, 2H), 7.36-7.32 (m, 1H), 5.61 (d, J=10.5 Hz, 1H), 4.08 (dd, J=11.7,2.8 Hz, 1H), 3.95-3.84 (m, 4H), 3.56 (td, J=11.9, 1.8 Hz, 1H), 3.36 (td,J=11.9, 1.8 Hz, 1H), 3.21 (s, 3H), 3.15-3.04 (m, 1H), 2.31 (s, 3H), 2.06(d, J=13.3 Hz, 1H), 1.63 (dd, J=13.4, 4.0 Hz, 1H), 1.46-1.34 (m, 1H),1.04 (d, J=13.0 Hz, 1H); LCMS (M+H)=534; HPLC RT=2.363 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Example 1955-{9-Fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,3-bromo-9-fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole(38.0 mg, 0.0730 mmol) was converted to the title compound (18.0 mg,45%). ¹H NMR (500 MHz, CDCl₃) δ 8.66 (d, J=1.7 Hz, 1H), 8.18 (s, 1H),7.71 (d, J=1.7 Hz, 1H), 7.62 (dd, J=8.7, 0.9 Hz, 1H), 7.46-7.42 (m, 2H),7.41-7.37 (m, 2H), 7.37-7.32 (m, 1H), 5.61 (d, J=10.5 Hz, 1H), 4.08 (dd,J=11.8, 2.8 Hz, 1H), 3.94-3.85 (m, 4H), 3.56 (td, J=11.9, 1.8 Hz, 1H),3.36 (td, J=11.9, 1.9 Hz, 1H), 3.21 (s, 3H), 3.15-3.05 (m, 1H), 2.06 (d,J=13.3 Hz, 1H), 1.68-1.59 (m, 1H), 1.41 (qd, J=12.4, 4.4 Hz, 1H), 1.04(d, J=13.0 Hz, 1H); LCMS (M+H)=537; HPLC RT=2.362 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Example 1965-{9-Fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-9-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indole(150 mg, 0.280 mmol) and4-(²H₃)methyl-5-(tributylstannyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole(194 mg, 0.420 mmol) were converted to the title compound (68.7 mg,44%). ¹H NMR (500 MHz, CDCl₃) δ 8.68 (d, J=1.5 Hz, 1H), 8.20 (s, 1H),7.91 (s, 1H), 7.80 (br t, J=7.2 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H),7.41-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.11-7.03 (m, 1H), 5.78 (br d,J=11.4 Hz, 1H), 4.07 (br dd, J=11.8, 2.8 Hz, 1H), 4.01 (s, 3H), 3.88 (brdd, J=11.7, 2.9 Hz, 1H), 3.59-3.51 (m, 1H), 3.38-3.29 (m, 1H), 3.23-3.11(m, 4H), 1.95 (br d, J=13.3 Hz, 1H), 1.66-1.60 (m, 1H), 1.39 (qd,J=12.3, 4.4 Hz, 1H), 0.99 (br d, J=12.8 Hz, 1H); LCMS (M+H)=555; HPLCRT=2.367 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Example 1975-{7-Methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

In an 8 mL vial was added5-{9-fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(20.0 mg, 0.0370 mmol) in MeOH (2 mL). To the mixture was added KOtBu(20.6 mg, 0.184 mmol), and the reaction was heated on an 80° C. heatingblock. After heating for 17 h, the reaction was cooled to roomtemperature and neutralized with 1M aq. citric acid. The mixture wasconcentrated to remove MeOH and diluted with water, then sat. aq. K₂CO₃was added, and the white precipitate was collected by filtration to givethe title compound (16.4 mg, 78%). ¹H NMR (500 MHz, CDCl₃) δ 8.65 (d,J=1.8 Hz, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.46-7.40 (m, 2H), 7.40-7.30(m, 4H), 5.60 (d, J=10.5 Hz, 1H), 4.27 (s, 3H), 4.07 (br dd, J=11.7, 2.8Hz, 1H), 3.91-3.82 (m, 4H), 3.60-3.51 (m, 1H), 3.39-3.30 (m, 1H), 3.21(s, 3H), 3.15-3.04 (m, 1H), 2.06 (br d, J=14.2 Hz, 1H), 1.69-1.60 (m,1H), 1.45-1.33 (m, 1H), 1.01 (br d, J=13.0 Hz, 1H); LCMS (M+H)=549; HPLCRT=2.273 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Example 1985-{5-[(S)-(2-Fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{7-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,5-{9-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(20.0 mg, 0.0360 mmol) was converted to the title compound (14.3 mg,66%). ¹H NMR (500 MHz, CDCl₃) δ 8.68 (d, J=1.7 Hz, 1H), 8.22-7.98 (m,1H), 7.93-7.74 (m, 2H), 7.39-7.29 (m, 3H), 7.08-7.00 (m, 1H), 5.76 (brd, J=11.0 Hz, 1H), 4.25 (s, 3H), 4.09-4.04 (m, 1H), 4.03-3.95 (m, 3H),3.89-3.81 (m, 1H), 3.58-3.51 (m, 1H), 3.37-3.29 (m, 1H), 3.17 (s, 4H),1.94 (br d, J=13.0 Hz, 1H), 1.43-1.33 (m, 1H), 0.97 (br d, J=14.2 Hz,1H); LCMS (M+H)=567; HPLC RT=2.297 min (Column: Chromolith ODS S5 4.6×50mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B:90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% Bover 4 min; Flow: 4 mL/min).

Examples 199 &2005-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Step 1:3-Bromo-5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indole

Following procedures analogous to those described for3-bromo-5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indole,3-bromo-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indole (50.0 mg,0.148 mmol) was converted to the title compound (71.0 mg, 88%). LCMS(M+H)=551; HPLC RT=3.045 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Step 2:5-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,3-bromo-5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indole(80.0 mg, 0.145 mmol) was converted to racemic5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,which was separated on chiral prep SFC to give enantiomer A (19.1 mg,22%) and enantiomer B (20.7 mg, 24%). Enantiomer A: ¹H NMR (500 MHz,CDCl₃) δ 8.67 (d, J=1.7 Hz, 1H), 8.17 (s, 1H), 7.72 (s, 1H), 7.62 (dd,J=8.7, 0.9 Hz, 1H), 7.45-7.32 (m, 5H), 5.61 (d, J=10.5 Hz, 1H), 3.92 (s,3H), 3.21 (s, 3H), 2.95 (q, J=11.2 Hz, 1H), 2.23 (br d, J=12.5 Hz, 2H),2.08-1.84 (m, 2H), 1.77-1.62 (m, 2H), 1.39 (qd, J=12.9, 3.5 Hz, 1H),1.27 (br d, J=10.2 Hz, 1H); LCMS (M+H)=571; HPLC RT=2.587 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFC RT=15.4 min(Column: Chiralpak IC, 250×4.6 mm, 5 μm; Mobile Phase: 55/45 CO₂/MeOH;Flow: 2 mL/min). Enantiomer B: ¹H NMR (500 MHz, CDCl₃) δ 8.67 (d, J=1.8Hz, 1H), 8.17 (s, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.62 (dd, J=8.7, 0.9 Hz,1H), 7.45-7.32 (m, 5H), 5.61 (d, J=10.7 Hz, 1H), 3.91 (s, 3H), 3.21 (s,3H), 2.95 (q, J=11.0 Hz, 1H), 2.23 (br d, J=12.7 Hz, 2H), 2.10-1.84 (m,2H), 1.76-1.59 (m, 2H), 1.44-1.34 (m, 1H), 1.28 (br s, 1H); LCMS(M+H)=571; HPLC RT=2.583 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min); SFC RT=17.5 min (Column: Chiralpak IC, 250×4.6 mm,5 μm; Mobile Phase: 55/45 CO₂/MeOH; Flow: 2 mL/min).

Example 2015-{9-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-bromo-9-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indole(72.7 mg, 0.136 mmol) and4-(²H₃)methyl-5-(tributylstannyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole(79.0 mg, 0.200 mmol) were converted to the title compound (40.5 mg,53%). ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=1.7 Hz, 1H), 8.14 (s, 1H),7.70 (d, J=1.7 Hz, 1H), 7.62 (dd, J=8.7, 1.0 Hz, 1H), 7.43 (dd, J=8.8,5.0 Hz, 2H), 7.13-7.04 (m, 2H), 5.57 (d, J=10.6 Hz, 1H), 4.08 (br dd,J=12.2, 2.5 Hz, 1H), 3.96 (s, 3H), 3.89 (br dd, J=11.9, 2.7 Hz, 1H),3.60-3.50 (m, 1H), 3.41-3.30 (m, 1H), 3.21 (s, 3H), 3.12-3.00 (m, 1H),2.01 (br d, J=12.3 Hz, 1H), 1.64-1.60 (m, 1H), 1.46-1.34 (m, 1H), 1.05(br d, J=12.2 Hz, 1H); LCMS (M+H)=555; HPLC RT=2.492 min (Column:Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1%TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Example 2025-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-9-methoxy-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Following procedures analogous to those described for5-{7-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,5-{9-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(30.0 mg, 0.0540 mmol) was converted to the title compound (25.6 mg,80%). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J=1.8 Hz, 1H), 7.95 (s, 1H),7.65 (s, 1H), 7.42 (dd, J=8.6, 5.1 Hz, 2H), 7.34 (s, 1H), 7.07 (t, J=8.5Hz, 2H), 5.56 (br d, J=10.5 Hz, 1H), 4.27 (s, 3H), 4.07 (br dd, J=11.7,2.6 Hz, 1H), 3.94 (s, 3H), 3.87 (br dd, J=11.6, 3.4 Hz, 1H), 3.54 (brtd, J=11.7, 1.6 Hz, 1H), 3.34 (td, J=11.9, 1.9 Hz, 1H), 3.21 (s, 3H),3.12-2.99 (m, 1H), 2.01 (br d, J=13.7 Hz, 1H), 1.68-1.60 (m, 1H), 1.38(qd, J=12.4, 4.7 Hz, 1H), 1.02 (br d, J=12.7 Hz, 1H); LCMS (M+H)=567;HPLC RT=2.443 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A:10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Examples 203 & 2042-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-bromo-5-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

Following procedures analogous to those described for3-bromo-5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indole,methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (45.0 mg, 0.147mmol) was converted to the title compound and was used withoutpurification in the next step without purification. LCMS (M+H)=513; HPLCRT=3.520 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 2: Methyl5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate

Following procedures analogous to those described for5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,methyl3-bromo-5-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylatewas converted to the title compound (25.4 mg, 32%). LCMS (M+H)=533; HPLCRT=3.128 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min).

Step 3:2-{5-[(4,4-Difluorocyclohexyl)(phenyl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following procedures analogous to those described for(S)-2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(25.4 mg, 0.0480 mmol) was converted to the racemic2-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated on chiral prep SFC to give enantiomer A (11.1 mg,42%) and enantiomer B (10.7 mg, 41%). Enantiomer A: ¹H NMR (500 MHz,CDCl₃) δ 8.45 (d, J=1.7 Hz, 2H), 8.00 (s, 1H), 7.60 (br s, 1H),7.49-7.41 (m, 3H), 7.38-7.34 (m, 2H), 7.33-7.29 (m, 1H), 5.61 (br d,J=10.5 Hz, 1H), 3.88 (s, 3H), 2.99-2.86 (m, 1H), 2.22 (br d, J=10.8 Hz,2H), 2.06-1.83 (m, 3H), 1.75 (d, J=2.7 Hz, 6H), 1.72-1.69 (m, 1H),1.45-1.31 (m, 2H); LCMS (M+H)=533; HPLC RT=2.783 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min); SFC RT=7.4 min (Column: Chiral IB,250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2 mL/min).Enantiomer B: ¹H NMR (500 MHz, CDCl₃) δ 8.44 (d, J=1.8 Hz, 1H), 8.35 (d,J=8.2 Hz, 1H), 7.97 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.47-7.41 (m, 3H),7.37-7.32 (m, 2H), 7.32-7.28 (m, 1H), 5.59 (d, J=10.5 Hz, 1H), 3.88 (s,3H), 2.99-2.89 (m, 1H), 2.21 (br d, J=12.7 Hz, 2H), 2.05-1.96 (m, 1H),1.96-1.83 (m, 2H), 1.75 (d, J=2.6 Hz, 6H), 1.62 (br s, 1H), 1.45-1.32(m, 2H); LCMS (M+H)=533; HPLC RT=2.781 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min); SFC RT=11.0 min (Column: Chiral IB,250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2 mL/min).

Examples 205 & 2062-{5-[(S)-(4,4-Difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following procedures analogous to those described for methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,methyl3-bromo-5-[(5)-(4,4-difluorocyclohexyl)(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(38.0 mg, 0.0740 mmol) was converted to the title compound (19.8 mg,50%). LCMS (M+H)=530; HPLC RT=3.128 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min).

Step 2:2-{5-[(S)-(4,4-Difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following procedures analogous to those described for(S)-2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(19.8 mg, 0.0370 mmol) was converted to racemic2-{5-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated on chiral prep SFC to give enantiomer A (7.90 mg,39%) and enantiomer B (8.20 mg, 40%). Enantiomer A: ¹H NMR (500 MHz,CDCl₃) δ 8.44 (d, J=1.7 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 7.97 (s, 1H),7.54 (d, J=1.8 Hz, 1H), 7.47-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.32-7.29(m, 1H), 5.59 (d, J=10.5 Hz, 1H), 3.88 (s, 3H), 2.99-2.89 (m, 1H), 2.30(s, 3H), 2.21 (br d, J=12.2 Hz, 2H), 2.06-1.96 (m, 1H), 1.96-1.83 (m,2H), 1.75 (d, J=2.7 Hz, 6H), 1.62 (br s, 1H), 1.45-1.33 (m, 2H); LCMS(M+H)=530; HPLC RT=2.785 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min); SFC RT=7.4 min (Column: Chiral IB, 250×4.6 mm, 5μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ¹H NMR(500 MHz, CDCl₃) δ 8.44 (d, J=1.8 Hz, 1H), 8.36 (d, J=7.9 Hz, 1H), 7.97(s, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.47-7.42 (m, 3H), 7.37-7.33 (m, 2H),7.32-7.29 (m, 1H), 5.59 (d, J=10.5 Hz, 1H), 3.88 (s, 3H), 2.94 (br q,J=11.0 Hz, 1H), 2.30 (s, 3H), 2.27-2.17 (m, 2H), 2.05-1.96 (m, 1H),1.96-1.83 (m, 2H), 1.75 (d, J=2.6 Hz, 6H), 1.64-1.59 (m, 1H), 1.44-1.32(m, 2H); LCMS (M+H)=530; HPLC RT=2.786 min (Column: Chromolith ODS S54.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile PhaseB: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 4 mL/min); SFC RT=11.0 min (Column: Chiral IB,250×4.6 mm, 5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2 mL/min).

Examples 207 & 2083-Fluoro-2-[{7-methanesulfonyl-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl}(oxan-4-yl)methyl]pyridine

Following procedures analogous to those described for5-{7-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,3-fluoro-2-({9-fluoro-7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl}(oxan-4-yl)methyl)pyridine(53.0 mg, 0.0930 mmol) was converted to the racemic3-fluoro-2-[{7-methanesulfonyl-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl}(oxan-4-yl)methyl]pyridine,which was separated on chiral prep SFC to give enantiomer A (4.00 mg,7%) and enantiomer B (4.0 mg, 7%). Enantiomer A: ¹H NMR (500 MHz, CDCl₃)δ 8.68 (d, J=1.7 Hz, 1H), 8.52 (br s, 1H), 8.28-8.04 (m, 1H), 7.45-7.39(m, 1H), 7.37-7.31 (m, 2H), 5.86 (br d, J=8.7 Hz, 1H), 4.25 (s, 3H),4.06 (s, 3H), 4.00 (br dd, J=11.7, 2.8 Hz, 1H), 3.83 (br dd, J=11.8, 3.0Hz, 1H), 3.51 (br t, J=11.1 Hz, 2H), 3.30 (br t, J=11.6 Hz, 1H), 3.21(br s, 3H), 1.71 (br d, J=10.4 Hz, 1H), 1.49 (qd, J=11.9, 4.0 Hz, 1H),1.40-1.28 (m, 1H), 0.86 (br d, J=12.1 Hz, 1H); LCMS (M+H)=568; HPLCRT=2.213 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1%TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4mL/min); SFC RT=5.1 min (Column: Chiral OJ-H, 250×4.6 mm, 5 μm; MobilePhase: 80/20 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ¹H NMR (500 MHz,CDCl₃) δ 8.68 (d, J=1.5 Hz, 1H), 8.52 (br s, 1H), 8.27-8.06 (m, 1H),7.45-7.40 (m, 1H), 7.37-7.31 (m, 2H), 5.86 (br d, J=7.5 Hz, 1H), 4.25(s, 3H), 4.06 (s, 3H), 4.00 (br dd, J=11.7, 3.0 Hz, 1H), 3.83 (br dd,J=11.8, 3.0 Hz, 1H), 3.51 (br t, J=11.4 Hz, 2H), 3.30 (br t, J=11.4 Hz,1H), 3.21 (br s, 3H), 1.71 (br d, J=11.3 Hz, 1H), 1.53-1.44 (m, 1H),1.39-1.29 (m, 1H), 0.91-0.82 (m, 1H); LCMS (M+H)=568; HPLC RT=2.208 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFCRT=6.9 min (Column: Chiral OJ-H, 250×4.6 mm, 5 μm; Mobile Phase: 80/20CO₂/MeOH; Flow: 2 mL/min).

Examples 209 & 2105-{5-[(S)-(4,4-Difluorocyclohexyl)(phenyl)methyl]-9-ethoxy-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

To a 20 mL vial containing KOtBu (72.4 mg, 0.645 mmol) in EtOH (3 mL)was added racemic5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(36.6 mg, 0.0640 mmol), and the reaction mixture was heated on an 80° C.heating block for 2 h. After cooling to room temperature, the reactionwas neutralized with 1M aq. cirtic acid and concentrated to remove EtOH.Water was added to the mixture, and the resulting white precipitate wascollected by filtration to give racemic5-{5-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-9-ethoxy-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,which was separated on chiral prep SFC to give enantiomer A (15.9 mg,41%) and enantiomer B (15.6 mg, 40%). Enantiomer A: ¹H NMR (500 MHz,CDCl₃) δ 8.64 (d, J=1.8 Hz, 1H), 7.93 (s, 1H), 7.62 (d, J=1.4 Hz, 1H),7.43-7.39 (m, 2H), 7.38-7.34 (m, 2H), 7.34-7.31 (m, 2H), 5.59 (d, J=10.5Hz, 1H), 4.55 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 3.20 (s, 3H), 2.93 (q,J=10.7 Hz, 1H), 2.24 (br d, J=11.0 Hz, 2H), 2.05-1.84 (m, 2H), 1.68 (t,J=7.0 Hz, 4H), 1.62 (br s, 1H), 1.41-1.31 (m, 1H), 1.28-1.20 (m, 1H);LCMS (M+H)=597; HPLC RT=2.760 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min); SFC RT=7.57 min (Column: Chiral OD-H, 250×4.6 mm,5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ¹HNMR (500 MHz, CDCl₃) δ 8.64 (d, J=1.8 Hz, 1H), 7.93 (s, 1H), 7.62 (d,J=1.4 Hz, 1H), 7.42-7.39 (m, 2H), 7.38-7.34 (m, 2H), 7.34-7.30 (m, 2H),5.59 (d, J=10.5 Hz, 1H), 4.55 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 3.20 (s,3H), 2.93 (q, J=10.8 Hz, 1H), 2.24 (br d, J=11.6 Hz, 2H), 2.05-1.82 (m,2H), 1.74-1.61 (m, 5H), 1.42-1.31 (m, 1H), 1.28-1.20 (m, 1H); LCMS(M+H)=597; HPLC RT=2.765 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min); SFC RT=8.96 min (Column: Chiral OD-H, 250×4.6 mm,5 μm; Mobile Phase: 80/20 CO₂/MeOH; Flow: 2 mL/min).

Examples 211 & 2122-[(4,4-Difluorocyclohexyl)({9-fluoro-7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine

Step 1:2-({3-Bromo-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indol-5-yl}(4,4-difluorocyclohexyl)methyl)-3-fluoropyridine

Following procedures analogous to those described for2-({3-bromo-9-fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indol-5-yl}(4,4-difluorocyclohexyl)methyl)-3-fluoropyridine,3-bromo-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indole (60.0 mg,0.175 mmol) was converted to the title compound and was used withoutpurification in the next step. LCMS (M+H)=570; HPLC RT=3.011 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2:2-[(4,4-Difluorocyclohexyl)({9-fluoro-7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine

Following procedures analogous to those described for5-{5-[(4,4-difluorocyclohexyl)(phenyl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,2-({3-bromo-9-fluoro-7-methanesulfonyl-5H-pyrido[3,2-b]indol-5-yl}(4,4-difluorocyclohexyl)methyl)-3-fluoropyridinewas converted to racemic2-[(4,4-difluorocyclohexyl)({9-fluoro-7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine(75.1 mg, 72% over 2 steps). Chiral separation was performed on theracemic compound (37.0 mg, 0.0630 mmol) using chiral prep SFC to giveenantiomer A (17.4 mg, 46%) and enantiomer B (17.4 mg, 46%). EnantiomerA: ¹H NMR (400 MHz, CDCl₃) δ 8.70 (d, J=1.7 Hz, 1H), 8.59-8.35 (m, 2H),7.61 (d, J=8.3 Hz, 1H), 7.48-7.41 (m, 1H), 7.39-7.33 (m, 1H), 5.88 (brd, J=10.5 Hz, 1H), 4.08 (s, 3H), 3.38 (br s, 1H), 3.21 (s, 3H), 2.16 (brs, 1H), 1.97 (br d, J=3.9 Hz, 1H), 1.88 (br d, J=14.7 Hz, 2H), 1.72-1.61(m, 1H), 1.49 (br d, J=11.4 Hz, 1H), 1.42-1.27 (m, 2H), 1.12 (br d,J=13.0 Hz, 1H); LCMS (M+H)=590; HPLC RT=2.608 min (Column: ChromolithODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; MobilePhase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 4 min; Flow: 4 mL/min); SFC RT=7.7 min (Column: Chiral AS,250×4.6 mm, 5 μm; Mobile Phase: 90/10 CO₂/MeOH; Flow: 2 mL/min).Enantiomer B: ¹H NMR (400 MHz, CDCl₃) δ 8.70 (d, J=1.7 Hz, 1H),8.60-8.33 (m, 2H), 7.61 (d, J=8.3 Hz, 1H), 7.49-7.41 (m, 1H), 7.40-7.34(m, 1H), 5.87 (br d, J=10.6 Hz, 1H), 4.08 (s, 3H), 3.38 (br s, 1H), 3.21(s, 3H), 2.23-2.11 (m, 1H), 2.05-1.80 (m, 3H), 1.72-1.61 (m, 1H),1.52-1.43 (m, 1H), 1.42-1.24 (m, 2H), 1.12 (br d, J=12.2 Hz, 1H); LCMS(M+H)=590; HPLC RT=2.606 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min); SFC RT=9.6 min (Column: Chiral AS, 250×4.6 mm, 5μm; Mobile Phase: 90/10 CO₂/MeOH; Flow: 2 mL/min).

Examples 213 &2142-[(4,4-Difluorocyclohexyl)({7-methanesulfonyl-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine

Following procedures analogous to those described for5-{7-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,racemic2-[(4,4-difluorocyclohexyl)({9-fluoro-7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine(37.0 mg, 0.0630 mmol) was converted to the racemic2-[(4,4-difluorocyclohexyl)({7-methanesulfonyl-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine,which was separated on chiral prep SFC to give enantiomer A (15.5 mg,40%) and enantiomer B (17.0 mg, 44%). Enantiomer A: ¹H NMR (400 MHz,CDCl₃) δ 8.69 (d, J=1.7 Hz, 1H), 8.53 (br s, 1H), 8.19 (br s, 1H),7.46-7.39 (m, 1H), 7.38-7.31 (m, 2H), 5.86 (br d, J=9.9 Hz, 1H), 4.25(s, 3H), 4.05 (s, 3H), 3.37 (br s, 1H), 3.21 (s, 3H), 2.14 (br s, 1H),2.02-1.79 (m, 3H), 1.70-1.59 (m, 1H), 1.51-1.44 (m, 1H), 1.39-1.25 (m,2H), 1.07 (br d, J=11.2 Hz, 1H); LCMS (M+H)=602; HPLC RT=2.575 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFCRT=7.8 min (Column: Chiral AS, 250×4.6 mm, 5 μm; Mobile Phase: 85/15CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ¹H NMR (400 MHz, CDCl₃) δ 8.69(d, J=1.7 Hz, 1H), 8.53 (br s, 1H), 8.19 (br s, 1H), 7.46-7.39 (m, 1H),7.38-7.32 (m, 2H), 5.86 (br d, J=11.1 Hz, 1H), 4.25 (s, 3H), 4.05 (s,3H), 3.38 (br s, 1H), 3.25-3.17 (m, 3H), 2.21-2.10 (m, 1H), 2.03-1.80(m, 3H), 1.71-1.60 (m, 1H), 1.48 (br d, J=14.2 Hz, 1H), 1.39-1.23 (m,2H), 1.08 (br d, J=11.7 Hz, 1H); LCMS (M+H)=602; HPLC RT=2.582 min(Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:waterwith 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFCRT=10.0 min (Column: Chiral AS, 250×4.6 mm, 5 μm; Mobile Phase: 85/15CO₂/MeOH; Flow: 2 mL/min).

Example 216

N-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl]methanesulfonamide

To a stirred solution of5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole(15.0 mg, 0.0280 mmol) and methanesulfonamide (15 mg, 0.158 mmol) in NMP(0.15 mL) was added t-BuOK (11.0 mg, 0.0980 mmol). This mixture washeated at 65° C. for 24 h and cooled to room temperature. The mixturewas diluted with 10% LiCl solution and extracted with EtOAc (2×). Theorganics were dried over MgSO₄, filtered, and concentrated. Theresulting residue was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge Phenyl, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 0-100% B over 20 min; Flow: 20 mL/min. Fractions containingthe desired product were combined and dried via centrifugal evaporationto give the title compound (1.6 mg, 9%). ¹H NMR (500 MHz, DMSO-d6) δ8.58 (br s, 1H), 8.27 (br s, 1H), 7.80 (br s, 1H), 7.55 (br d, J=7.7 Hz,2H), 7.43 (br d, J=7.4 Hz, 1H), 7.36-7.27 (m, 3H), 7.25-7.20 (m, 1H),6.71 (br d, J=10.4 Hz, 1H), 3.84 (br d, J=8.8 Hz, 1H), 3.73 (s, 3H),3.62 (br s, 1H), 3.58 (br s, 3H), 3.46 (br t, J=11.3 Hz, 1H), 3.27 (brd, J=10.4 Hz, 1H), 3.18 (br t, J=11.8 Hz, 1H), 2.54 (s, 3H), 2.00 (s,3H), 1.93 (br s, 1H), 1.66-1.50 (m, 2H), 0.44 (br d, J=11.8 Hz, 1H).LCMS: RT=1.64 min; (ES): m/z (M+H)⁺=609.4; LCMS: Column: Waters AcquityUPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min. HPLC Purity at 220 nm: 100%.

Examples 217-219

The compounds in Table 7 were prepared according to the proceduredescribed above (Example 216):

TABLE 7 HPLC RT LCMS HPLC Example R (min) (M + H) Method 217

1.53 623.0 B 218

1.72 635.2 B 219

1.83 649.4 B

-   -   HPLC Conditions for Table 7: Method B: Column: Waters Acquity        UPLC BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95        acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:        95:5 acetonitrile:water with 10 mM ammonium acetate;        Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a        0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220        nm.

Example 2215-{9-Fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

In a 4 mL vial,(S)-3-bromo-9-fluoro-6-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(150 mg, 0.290 mmol),4-(²H₃)methyl-5-(tributylstannyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole(241 mg, 0.522 mmol), and tetrakis(triphenylphosphine) palladium (0)(40.2 mg, 0.0350 mmol) were dissolved in DMF (1.00 mL) to give an orangesuspension. Copper (I) iodide (8.28 mg, 0.0430 mmol) and Et₃N (0.0890mL, 0.638 mmol) were added. The reaction mixture was purged withnitrogen for 5 min and then heated at 95° C. for 40 min. The mixture wascooled to room temperature and combined with 1M nBu₄NF in THF (1.16 mL,1.16 mmol). The resulting mixture was stirred at room temperature for 30min, and diluted with EtOAc. The mixture was washed with 10% aq. LiClsolution and brine. The organic layer was dried (MgSO₄), filtered, andconcentrated to give the crude mixture. This mixture was purified bysilica gel column chromatography (Teledyne ISCO CombiFlash 0% to 100%solvent A/B=hexane/EtOAc, RediSep SiO₂ 80 g, detecting at 254 nM, andmonitoring at 220 nM). Concentration of appropriate fractions provided5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(156 mg, 65%). 1H NMR ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.38(dd, J=8.8, 5.0 Hz, 1H), 7.88 (s, 1H), 7.62 (br d, J=7.7 Hz, 2H), 7.41(t, J=8.9 Hz, 1H), 7.37-7.31 (m, 2H), 7.29-7.23 (m, 1H), 6.79 (br d,J=10.4 Hz, 1H), 3.93-3.82 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.65 (brd, J=8.8 Hz, 1H), 3.54-3.46 (m, 1H), 3.40 (br s, 1H), 3.24-3.13 (m, 1H),1.96 (br d, J=13.1 Hz, 1H), 1.77-1.56 (m, 2H), 0.46 (br d, J=12.5 Hz,1H).). LCMS: RT=1.572 min; (ES): m/z (M+H)⁺=537.10; LCMS: Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min. HPLC Purity at 220 nm: 99%.

Example 222N-{6-Methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl}cyclopropanesulfonamide

To a stirred solution of5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(25.0 mg, 0.0500 mmol) and cyclopropanesulfonamide (22.6 mg, 0.190 mmol)in NMP (0.25 mL) was added t-BuOK (18.3 mg, 0.160 mmol). This mixturewas heated at 65° C. for 17 h before it was cooled to room temperature.The mixture was then diluted with 10% aq. LiCl solution and extractedwith EtOAc. Combined EtOAc extracts were dried (MgSO₄), filtered, andconcentrated to give the crude mixture. It was purified via preparativeLC/MS with the following conditions: Column: Waters XBridge Phenyl,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 15-70% B over 20 min, then a 5-minhold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveN-{6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl}cyclopropanesulfonamide(14.7 mg, 50%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.34 (d, J=8.8Hz, 1H), 7.95-7.91 (m, 1H), 7.63 (br d, J=7.7 Hz, 2H), 7.53 (d, J=8.8Hz, 1H), 7.37-7.31 (m, 2H), 7.30-7.22 (m, 1H), 6.76 (s, 1H), 3.88 (br d,J=16.2 Hz, 1H), 3.79 (s, 3H), 3.68 (br s, 1H), 3.64 (s, 3H), 3.51 (br d,J=12.1 Hz, 1H), 3.43 (br d, J=10.1 Hz, 1H), 3.25-3.20 (m, 1H), 3.15 (brd, J=4.4 Hz, 1H), 2.54 (s, 1H), 1.95 (br d, J=12.5 Hz, 1H), 1.64 (br d,J=8.4 Hz, 2H), 1.21 (br s, 2H), 1.10 (br d, J=8.1 Hz, 2H), 0.51 (br d,J=12.1 Hz, 1H). LCMS: RT=1.792 min; (ES): m/z (M+H)⁺=638.15; LCMS:Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min. HPLC Purity at 220 nm: 98%.

Example 223

The compound in Table 8 was prepared according to the proceduredescribed above (Example 222):

TABLE 8 HPLC RT LCMS HPLC Example R (min) (M + H) Method 223

1.75 626.1 B

-   -   HPLC Conditions for Table 8: Method B: Column: Waters Acquity        UPLC BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95        acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:        95:5 acetonitrile:water with 10 mM ammonium acetate;        Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a        0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220        nm.

Example 2254-({6-Methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl}amino)butanoicacid

To a stirred solution of5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(20.0 mg, 0.0400 mmol) and pyrrolidin-2-one (0.100 mL, 0.0400 mmol) inNMP (0.10 mL) was added t-BuOK (20.0 mg, 0.180 mmol). This mixture washeated at 95° C. for 2 h and cooled to room temperature. The mixture wasdiluted with MeOH and purified via preparative LC/MS with the followingconditions: Column: Waters XBridge Phenyl, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 15-70% B over 20 min, then a 5-min hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to give4-({6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl}amino)butanoicacid (5.80 mg, 25%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (s, 1H), 8.20 (brs, 1H), 8.10 (br d, J=8.8 Hz, 1H), 7.76 (s, 1H), 7.57 (br d, J=7.4 Hz,2H), 7.37-7.27 (m, 2H), 7.27-7.22 (m, 1H), 6.77-6.69 (m, 2H), 3.87 (brd, J=9.8 Hz, 1H), 3.75 (s, 3H), 3.67 (br d, J=10.4 Hz, 1H), 3.52 (br s,1H), 3.46 (s, 1H), 3.36 (br s, 1H), 3.20 (br t, J=11.8 Hz, 1H), 2.54 (s,5H), 2.40 (br t, J=7.1 Hz, 2H), 1.98-1.88 (m, 3H), 1.72-1.53 (m, 2H),0.53 (br d, J=11.8 Hz, 1H). LCMS: RT=1.328 min; (ES): m/z (M+H)⁺=620.10.LCMS: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min. HPLC Purity at 220 nm: 98%.

Example 226N-(2-Amino-2-methylpropyl)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-amine

To a stirred solution of5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(22.0 mg, 0.0410 mmol) and 3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dione(44.1 mg, 0.290 mmol) in NMP (0.10 mL) was added t-BuOK (32.0 mg, 0.280mmol). This mixture was gradually heated to 95° C. for 3 h and cooled toroom temperature. The mixture was diluted with MeOH and purified viapreparative LC/MS with the following conditions: Column: Waters XBridgePhenyl, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-70% B over20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to giveN-(2-amino-2-methylpropyl)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-amine(8.60 mg, 35%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.42 (br t,J=6.1 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 7.66 (s, 1H), 7.54 (br d, J=7.7Hz, 2H), 7.35-7.29 (m, 2H), 7.26-7.19 (m, 1H), 6.75 (d, J=9.1 Hz, 1H),6.70 (br d, J=10.1 Hz, 1H), 3.85 (br d, J=14.5 Hz, 1H), 3.71 (br s, 2H),3.65 (br s, 3H), 3.60 (br d, J=6.7 Hz, 1H), 3.51-3.45 (m, 1H), 3.42 (s,2H), 3.30 (br d, J=9.4 Hz, 1H), 3.19 (br t, J=11.8 Hz, 1H), 2.54 (s,3H), 1.95 (br d, J=12.1 Hz, 1H), 1.72-1.63 (m, 1H), 1.60 (br d, J=12.1Hz, 1H), 1.27 (s, 6H), 0.51 (br d, J=12.5 Hz, 1H). LCMS: RT=1.299 min;(ES): m/z (M+H)⁺=605.15; LCMS: Column: Waters Acquity UPLC BEH C18,2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% Bover 3 min, then a 0.75-min hold at 100% B; Flow: 1.11 mL/min. HPLCPurity at 220 nm: 100%.

Example 2276-Methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-amine

5-{9-Fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(8.00 mg, 0.0200 mmol) was mixed with 0.5 M NH₃ in dioxane (0.200 mL,0.100 mmol). This mixture was heated to 95° C. for 7 h and cooled toroom temperature. To this mixture was then added 0.5 M NH₃ in dioxane(0.500 mL, 0.250 mmol) and heated at 125° C. for 14 h in a pressurized,sealed vial. The mixture was cooled to room temperature and diluted withMeOH. It was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge Phenyl, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 15-70% B over 20 min, then a 5-min hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to give6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-amine(4.60 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.01 (d, J=8.8Hz, 1H), 7.74 (s, 1H), 7.57 (br d, J=7.7 Hz, 2H), 7.50 (s, 2H),7.35-7.28 (m, 2H), 7.27-7.21 (m, 1H), 6.73 (br d, J=10.1 Hz, 1H), 6.64(s, 1H), 3.87 (br d, J=9.1 Hz, 1H), 3.75 (s, 3H), 3.68 (br d, J=8.4 Hz,1H), 3.55-3.47 (m, 1H), 3.46-3.41 (m, 1H), 3.21 (br t, J=11.6 Hz, 1H),2.54 (s, 3H), 1.94 (br d, J=13.5 Hz, 1H), 1.73-1.56 (m, 2H), 0.55 (br d,J=12.5 Hz, 1H). LCMS: RT=1.586 min; (ES): m/z (M+H)⁺=534.10, LCMS:Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min. HPLC Purity at 220 nm: 99%.

Example 2282,2,2-Trifluoro-N-{6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl}ethane-1-sulfonamide

To a stirred solution of6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-amine(41.2 mg, 0.0800 mmol) in DCE (1.00 mL) was added DIEA (0.200 mL, 1.15mmol) and 2,2,2-trifluoroethanesulfonyl chloride (0.0500 mL, 0.450mmol). The mixture was stirred at room temperature for 45 min anddiluted with EtOAc. The resulting mixture was washed with saturated aq.NaHCO₃ solution and brine. The EtOAc layer was dried (MgSO₄), filtered,and concentrated. The crude product was purified via preparative LC/MSwith the following conditions: Column: Waters XBridge Phenyl, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-70% B over 20 min, then a 5-min hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give2,2,2-trifluoro-N-{6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl}ethane-1-sulfonamide(2.19 mg, 3%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.35 (br d,J=8.8 Hz, 1H), 7.98 (s, 1H), 7.63 (br d, J=7.7 Hz, 2H), 7.53 (br d,J=8.7 Hz, 1H), 7.34 (br t, J=7.4 Hz, 2H), 7.29-7.22 (m, 1H), 6.77 (br d,J=10.4 Hz, 1H), 5.14 (br d, J=9.5 Hz, 2H), 3.87 (br d, J=6.6 Hz, 1H),3.79 (s, 3H), 3.75 (br s, 1H), 3.66-3.61 (m, 1H), 3.50 (br t, J=10.6 Hz,1H), 3.40 (br d, J=18.8 Hz, 1H), 3.21 (br t, J=11.6 Hz, 1H), 2.54 (s,3H), 1.94 (br d, J=11.9 Hz, 1H), 1.70-1.58 (m, 2H), 0.50 (br d, J=12.1Hz, 1H). LCMS: RT=1.791 min; (ES): m/z (M+H)⁺=680.10. LCMS: Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min. HPLC Purity at 220 nm: 99%.

Example 2295-[9-(2,2-Difluoroethoxy)-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

To a stirred solution of5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(28.0 mg, 0.0500 mmol) and 2,2-difluoroethanol (37.0 mg, 0.450 mmol) inNMP (0.30 mL) was added t-BuOK (112 mg, 0.210 mmol). This mixture washeated at 65° C. for 5 h and cooled to room temperature. The mixture wasdiluted with MeOH and purified via preparative LC/MS with the followingconditions: Column: Waters XBridge Phenyl, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 15-70% B over 20 min, then a 5-min hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to give5-[9-(2,2-difluoroethoxy)-6-methanesulfonyl-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(6.50 mg. 20%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.29 (d, J=9.1Hz, 1H), 7.76 (s, 1H), 7.56 (br d, J=7.7 Hz, 2H), 7.38-7.29 (m, 2H),7.28-7.22 (m, 1H), 7.20 (d, J=9.1 Hz, 1H), 6.75 (br d, J=10.1 Hz, 1H),6.69-6.39 (m, 1H), 4.78-4.67 (m, 2H), 3.85 (br d, J=9.1 Hz, 1H), 3.74(s, 3H), 3.62 (br s, 1H), 3.49 (br t, J=11.4 Hz, 1H), 3.34 (br d, J=10.8Hz, 1H), 3.18 (br t, J=11.8 Hz, 1H), 2.54 (s, 3H), 1.96 (br d, J=12.5Hz, 1H), 1.77-1.66 (m, 1H), 1.63-1.51 (m, 1H), 0.42 (br d, J=12.1 Hz,1H) LCMS: RT=1.594 min; (ES): m/z (M+H)⁺=599.05, LCMS: Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min. HPLC Purity at 220 nm: 95%.

Example 2305-[9-(2,2-Difluoropropoxy)-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-4-(2H₃)methyl-1-methyl-1H-1,2,3-triazole

To a stirred solution of5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(31.0 mg, 0.0600 mmol) and 2,2-difluoropropan-2-ol (27.8 mg, 0.290 mmol)in NMP (0.30 mL) was added t-BuOK (25.9 mg, 0.230 mmol). This mixturewas heated at 65° C. for 1 h and cooled to room temperature. The mixturewas diluted with MeOH and purified via preparative LC/MS with thefollowing conditions: Column: Waters XBridge Phenyl, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 15-70% B over 20 min, then a 5-min hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to give5-[9-(2,2-difluoropropoxy)-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(13.8 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.29 (d, J=8.8Hz, 1H), 7.74 (s, 1H), 7.56 (br d, J=7.7 Hz, 2H), 7.36-7.29 (m, 2H),7.28-7.22 (m, 1H), 7.18 (d, J=8.9 Hz, 1H), 6.74 (s, 1H), 4.67 (br t,J=12.0 Hz, 2H), 3.86 (br d, J=15.1 Hz, 1H), 3.73 (s, 3H), 3.60-3.55 (m,1H), 3.49 (br t, J=11.5 Hz, 1H), 3.33 (br d, J=11.8 Hz, 1H), 3.23-3.16(m, 1H), 2.54 (s, 3H), 1.95 (br t, J=19.4 Hz, 3H), 1.69 (br d, J=10.8Hz, 1H), 1.62-1.50 (m, 1H), 1.22 (br d, J=8.8 Hz, 1H), 0.43 (br d,J=12.0 Hz, 1H). LCMS: RT=1.731 min; (ES): m/z (M+H)⁺=613.15, LCMS:Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min. HPLC Purity at 220 nm: 95%.

Example 2315-{9-Fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Step 1:(S)-3-Bromo-9-fluoro-5-((2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole

To a stirred solution of3-bromo-9-fluoro-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole (100 mg,0.290 mmol) and (R)-(2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol(123 mg, 0.580 mmol) in toluene (2.0 mL) was added triphenylphosphine(153 mg, 0.580 mmol) and DIAD (0.110 mL, 0.580 mmol). The mixture wasstirred at room temperature for 2 h and was then directly purified bysilica gel column chromatography (Teledyne ISCO CombiFlash 0% to 100%solvent A/B=hexane/EtOAc, RediSep SiO₂ 24 g, detecting at 254 nM, andmonitoring at 220 nM). Concentration of appropriate fractions provided(S)-3-bromo-9-fluoro-5-[(S)-2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indole(156 mg) in a quantitative yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s,1H), 8.64 (d, J=1.8 Hz, 1H), 8.42 (dd, J=8.9, 5.4 Hz, 1H), 8.17-8.12 (m,1H), 8.11 (d, J=1.8 Hz, 1H), 7.40 (t, J=8.9 Hz, 1H), 7.37-7.31 (m, 1H),7.07-6.99 (m, 1H), 6.96 (d, J=10.4 Hz, 1H), 4.77 (dt, J=12.3, 6.2 Hz,1H), 3.89 (br d, J=10.5 Hz, 1H), 3.73 (br dd, J=11.0, 2.9 Hz, 1H),3.64-3.58 (m, 1H), 3.56 (s, 3H), 3.40-3.33 (m, 1H), 1.93-1.66 (m, 3H),0.70 (br d, J=11.9 Hz, 1H). HPLC: RT=2.771 min (Chromolith ODS 4.6×50 mm(4 min grad) eluting with 10-90% aqueous MeOH over 4 min containing 0.1%TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z=535, 537 (Br pattern)[M+H]⁺.

Step 2:5-{9-Fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

To a stirred solution of(S)-3-bromo-9-fluoro-5-((2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(216 mg, 0.400 mmol) and4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1-H-1,2,3-triazole (283 mg,0.730 mmol) in DMF (4.0 mL) was added Et₃N (0.120 mL, 0.880 mmol), andthe mixture was purged with nitrogen. While purging, copper (I) iodide(11.5 mg, 0.0600 mmol) and tetrakis(triphenylphosphine) palladium (0)(55.9 mg, 0.0500 mmol) were added. The reaction mixture was purged withnitrogen for another 5 min and then heated at 95° C. for 40 min. Themixture was cooled to room temperature, diluted with MeOH, and purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge Phenyl, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-70% B over20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give5-{9-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(9.50 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.42 (dd,J=8.8, 5.3 Hz, 1H), 8.14-8.07 (m, 1H), 7.98 (s, 1H), 7.41 (t, J=8.8 Hz,1H), 7.36-7.29 (m, 2H), 7.05-6.99 (m, 1H), 6.96 (br d, J=10.4 Hz, 1H),3.88 (br d, J=9.8 Hz, 1H), 3.75 (s, 3H), 3.71 (br s, 1H), 3.57 (br s,2H), 3.27 (br t, J=11.3 Hz, 1H), 2.54 (s, 3H), 1.95-1.84 (m, 1H),1.83-1.69 (m, 2H), 0.74 (br d, J=12.3 Hz, 1H). LCMS: RT=1.577 min; (ES):m/z (M+H)+=555.15. LCMS: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min,then a 0.75-min hold at 100% B; Flow: 1.11 mL/min. HPLC Purity at 220nm: 97%. LCMS: RT=1.577 min; (ES): m/z (M+H)⁺=555.15.

Example 2335-{9-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Step 1:3-Bromo-9-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indole

To a stirred solution of3-bromo-9-fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indole (100 mg, 0.290mmol) and (R)-(4-fluorophenyl)(tetrahydor-2H-pyran-4-yl)methanol (123mg, 0.580 mmol) in toluene (2.0 mL) was added triphenylphosphine (153mg, 0.580 mmol) and DIAD (0.110 mL, 0.580 mmol). The mixture was stirredat room temperature for 3 h and was then directly purified by silica gelcolumn chromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=hexane/EtOAc, RediSep SiO₂ 24 g, detecting at 254 nM, and monitoringat 220 nM). Concentration of appropriate fractions provided3-bromo-9-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indole(156 mg) in a quantitative yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s,1H), 8.66 (d, J=1.8 Hz, 1H), 8.36 (dd, J=8.9, 5.3 Hz, 1H), 7.97 (d,J=1.8 Hz, 1H), 7.71 (dd, J=8.6, 5.4 Hz, 1H), 7.39 (t, J=8.9 Hz, 1H),7.19 (t, J=8.9 Hz, 1H), 6.71 (d, J=10.4 Hz, 1H), 4.77 (dt, J=12.4, 6.2Hz, 1H), 3.86 (br dd, J=11.0, 2.7 Hz, 1H), 3.71 (s, 3H), 3.63 (br dd,J=11.1, 3.2 Hz, 1H), 3.55 (br t, J=11.0 Hz, 1H), 3.35 (br s, 1H),3.26-3.15 (m, 1H), 1.91 (br d, J=13.4 Hz, 1H), 1.71-1.47 (m, 1H), 1.23(br d, J=3.4 Hz, 1H), 0.36 (br d, J=11.9 Hz, 1H). HPLC: RT=2.935 min(Chromolith ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOHover 4 min containing 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=535, 537 (Br pattern) [M+H]⁺.

Step 2:5-{9-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

To a stirred solution of3-bromo-9-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indole(233 mg, 0.430 mmol) in DMF (4.0 mL) was added Et₃N (0.140 mL, 0.960mmol), and the mixture was purged with nitrogen. While purging, copper(I) iodide (12.4 mg, 0.0700 mmol) and tetrakis(triphenylphosphine)palladium (0) (60.3 mg, 0.0500 mmol) were added. The reaction mixturewas purged with nitrogen for another 5 min and then heated at 95° C. for15 h. The mixture was cooled to room temperature, diluted with MeOH, andpurified via preparative LC/MS with the following conditions: Column:Waters XBridge Phenyl, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-70% B over20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give5-{9-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(50.3 mg, 21%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.37 (br dd,J=8.6, 5.0 Hz, 1H), 7.89 (s, 1H), 7.70-7.64 (m, 2H), 7.40 (br t, J=8.7Hz, 1H), 7.17 (br t, J=8.6 Hz, 2H), 6.75 (br d, J=10.2 Hz, 1H), 3.86 (brd, J=9.5 Hz, 1H), 3.82 (s, 3H), 3.64 (br d, J=8.8 Hz, 1H), 3.53-3.51 (m,1H), 3.37 (br s, 1H), 3.18 (br t, J=11.4 Hz, 1H), 2.54 (s, 3H), 1.90 (brs, 1H), 1.69-1.54 (m, 2H), 0.46 (br d, J=12.0 Hz, 1H). LCMS: RT=1.604min; (ES): m/z (M+H)⁺=555.15, LCMS: Column: Waters Acquity UPLC BEH C18,2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% Bover 3 min, then a 0.75-min hold at 100% B; Flow: 1.11 mL/min. HPLCPurity at 220 nm: 99%.

Examples 235 & 2363-Fluoro-2-({9-fluoro-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl}(oxan-4-yl)methyl)pyridine

Step 1:5-(9-Fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl)-4-(²H₃)methyl-1-methyl-1H-1,2,3-trizole

To a stirred solution of3-bromo-9-fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indole (50.0 mg,0.150 mmol) and4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1-H-1,2,3-triazole (102 mg,0.260 mmol) in DMF (1.00 mL) was added Et₃N (0.0500 mL, 0.320 mmol).While purging with nitrogen, the mixture was combined with copper (I)iodide (4.16 mg, 0.0200 mmol) and tetrakis(triphenylphosphine) palladium(0) (20.2 mg, 0.0200 mmol). The mixture was heated at 95° C. for 7 h.The reaction mixture was cooled to room temperature. To this cooledmixture was added4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1-H-1,2,3-triazole (102 mg,0.260 mmol), Et₃N (0.0500 mL, 0.320 mmol), copper (I) iodide (4.16 mg,0.0200 mmol) and tetrakis(triphenylphosphine) palladium (0) (20.2 mg,0.0200 mmol) under nitrogen. The mixture was then heated at 95° C. for14 h and cooled to room temperature. The mixture was diluted with 10%aq. LiCl solution and extracted with EtOAc. Combined EtOAc extracts werewashed with brine, dried (MgSO₄), filtered, and concentrated to give thecrude mixture. The crude product was purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 100% solvent A/B=DCM/10%MeOH in DCM, RediSep SiO₂ 24 g, detecting at 254 nM, and monitoring at220 nM). Concentration of appropriate fractions provided5-(9-fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl)-4-(²H₃)methyl-1-methyl-1H-1,2,3-trizole(25.0 mg, 47%). ¹H NMR (400 MHz, CDCl₃) δ 10.99 (br s, 1H), 8.64 (s,1H), 8.08 (dd, J=8.6, 4.6 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.20 (t,J=8.9 Hz, 1H), 4.05 (s, 3H), 3.25 (s, 3H), HPLC: RT=0.65 min (ChromolithODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z=363.1[M+H]⁺.

Step 2:3-Fluoro-2-({9-fluoro-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl}(oxan-4-yl)methyl)pyridine

To a stirred solution of5-(9-fluoro-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl)-4-(²H₃)methyl-1-methyl-1H-1,2,3-trizole1 (25.0 mg, 0.0700 mmol) and(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (29.1 mg, 0.140mmol) in toluene (0.5 mL) was added triphenylphosphine (36.2 mg, 0.140mmol) and DIAD (0.0270 mL, 0.140 mmol). The mixture was stirred at roomtemperature was monitored by LCMS until the reaction was complete. Thereaction mixture was then directly purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=DCM/EtOAc, RediSep SiO₂ 12 g, detecting at 254 nM, and monitoring at220 nM). Concentration of appropriate fractions provided racemic3-fluoro-2-({9-fluoro-6-methanesulfonyl-3-[4-(²H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl}(oxan-4-yl)methyl)pyridine(14.0 mg). This racemic mixture was separated by chiral prep SFC (BergerSFC MGII, Column: Chiral OD-H 25×3 cm ID, 5 μm Flow rate:85.0 mL/min.Mobile Phase:70/30 CO₂/MeOH Detector Wavelength: 220 nm) to giveEnantiomer A (5.20 mg, 14%) and Enantiomer B (4.00 mg, 10%). EnantiomerA: ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d, J=1.8 Hz, 1H), 8.49 (dt, J=4.2,1.6 Hz, 1H), 8.45 (dd, J=8.9, 5.4 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H),7.42-7.33 (m, 2H), 7.30-7.29 (m, 1H), 7.25-7.18 (m, 1H), 4.06-3.98 (m,1H), 3.96 (s, 3H), 3.83 (br dd, J=11.6, 3.4 Hz, 1H), 3.48 (td, J=11.4,3.1 Hz, 1H), 3.42 (s, 3H), 3.23-3.22 (m, 1H), 3.22 (td, J=11.9, 2.0 Hz,1H), 1.96-1.88 (m, 1H), 1.84-1.74 (m, 2H), 0.56 (br d, J=11.4 Hz, 1H).LCMS (M+H)=556.2; SFC RT=6.457 min (Column: Chiralcel OD-H 250×4.6 mm, 5μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min); Enantiomer B: ¹H NMR(400 MHz, CDCl₃) δ 8.64 (d, J=1.8 Hz, 1H), 8.49 (dt, J=4.2, 1.6 Hz, 1H),8.45 (dd, J=8.9, 5.4 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.42-7.33 (m, 2H),7.30-7.29 (m, 1H), 7.25-7.18 (m, 1H), 4.06-3.98 (m, 1H), 3.96 (s, 3H),3.83 (br dd, J=11.6, 3.4 Hz, 1H), 3.48 (td, J=11.4, 3.1 Hz, 1H), 3.42(s, 3H), 3.23-3.22 (m, 1H), 3.22 (td, J=11.9, 2.0 Hz, 1H), 1.96-1.88 (m,1H), 1.84-1.74 (m, 2H), 0.56 (br d, J=11.4 Hz, 1H) LCMS (M+H)=556.2; SFCRT=8.286 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase:70/30 CO₂/MeOH; Flow: 2 mL/min).

Examples 239 & 2402-[(4,4-Difluorocyclohexyl)({7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine

Step 1: 4,4-Difluorocyclohexyl)(3-fluoropyridin-2-yl)methanone

To a stirred solution of 2-bromo-3-fluoropyridine (2.00 g, 11.4 mmol) inTHF (20 mL) under nitrogen in an acetone-dry ice bath was added nBuLi(2.5M in hexane, 5.00 mL, 12.5 mmol) slowly over 15 min through the sideof the reaction flask. The mixture was stirred at −78° C. under nitrogenfor 95 min. At that time, a solution of4,4-difluoro-N-methoxy-N-methylcyclohexanecarboxamide (2.35 g, 11.4mmol) in THF (4 mL) was added over 5 min. The mixture was stirred at−78° C. for 10 min and at room temperature for 15 min. The mixture wasquenched with saturated aq. NH₄Cl solution and extracted with EtOAc. TheEtOAc extract was washed with brine, dried (MgSO₄), filtered, andconcentrated. The crude mixture was purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 30% solventA/B=DCM/EtOAc, RediSep SiO₂ 40 g, detecting at 254 nM, and monitoring at220 nM). Concentration of appropriate fractions provided4,4-difluorocyclohexyl)(3-fluoropyridin-2-yl)methanone (722 mg, 2.97mmol, 26%). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (dt, J=4.1, 1.5 Hz, 1H),7.59-7.42 (m, 2H), 3.83-3.72 (m, 1H), 2.27-2.10 (m, 2H), 2.00 (br dd,J=7.2, 3.1 Hz, 2H), 1.92-1.78 (m, 4H). HPLC: RT=1.937 min (ChromolithODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z=244.1[M+H]⁺.

Step 2: (4,4-Difluorocyclohexyl)(phenyl)methanol

To a stirred solution of(4,4-difluorocyclohexyl)(3-fluoropyridin-2-yl)methanone (0.920 g, 3.78mmol) in MeOH (10.0 mL) at 0° C. was added NaBH₄ (0.215 g, 5.67 mmol)portionwise over 5 min. The mixture was stirred in the ice water bathfor 20 min and quenched with water. The resulting mixture was extractedwith EtOAc. Combined EtOAc extracts were washed with saturated aq.NaHCO₃ solution and brine. The organic layer was dried (MgSO₄),filtered, and concentrated to give(4,4-difluorocyclohexyl)(phenyl)methanol (0.860 g, 93%), ¹H NMR (400MHz, DMSO-d₆) δ 8.42 (dt, J=4.6, 1.5 Hz, 1H), 7.68 (ddd, J=10.4, 8.4,1.3 Hz, 1H), 7.40 (dt, J=8.4, 4.3 Hz, 1H), 5.30 (d, J=6.4 Hz, 1H),4.62-4.52 (m, 1H), 2.09-1.87 (m, 3H), 1.84-1.57 (m, 2H), 1.40-1.08 (m,4H). HPLC: RT=0.72 min (Chromolith ODS 4.6×50 mm (4 min grad) elutingwith 10-90% aqueous MeOH over 4 min containing 0.1% TFA, 4 mL/min,monitoring at 220 nm); MS (ES): m/z=246.1 [M+H]⁺.

Step 3:5-((4,4-Difluorocyclohexyl)(4-fluoropyridin-3-yl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole

To a stirred solution of3-bromo-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole (60.0 mg, 0.185 mmol)and (4,4-difluorocyclohexyl)(3-fluoropyridin-2-yl)methanol (91.0 mg,0.369 mmol) in toluene (2.0 mL) was added triphenylphosphine (97.0 mg,0.369 mmol) and DIAD (0.0720 mL, 0.369 mmol). The mixture was stirred atroom temperature for 1.5 h and was then directly purified by silica gelcolumn chromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=DCM/EtOAc, RediSep SiO₂ 24 g, detecting at 254 nM, and monitoring at220 nM). Concentration of appropriate fractions provided5-((4,4-difluorocyclohexyl)(4-fluoropyridin-3-yl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole(102 mg) in quantitative yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (d,J=1.8 Hz, 1H), 8.67 (s, 1H), 8.62 (br d, J=4.6 Hz, 1H), 8.41 (d, J=8.2Hz, 1H), 7.82 (br d, J=8.2 Hz, 1H), 7.74-7.64 (m, 1H), 7.51 (dt, J=8.6,4.4 Hz, 1H), 7.46-7.30 (m, 1H), 6.32 (br d, J=11.1 Hz, 1H), 5.48-5.23(m, 1H), 4.87 (dd, J=12.6, 6.4 Hz, 1H), 4.78 (ddd, J=18.6, 12.4, 6.3 Hz,1H), 4.45-4.20 (m, 1H), 3.29 (br s, 3H), 1.45-1.34 (m, 1H), 1.23 (br d,J=3.5 Hz, 2H), 1.21-1.12 (m, 2H). HPLC: RT=3.036 min (Chromolith ODS4.6×50 mm (4 min gradiant) eluting with 10-90% aqueous MeOH over 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z=552.0[M+H]⁺.

Step 4:2-[(4,4-Difluorocyclohexyl)({7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine

To a stirred solution of3-bromo-5-((4,4-difluorocyclohexyl)(4-fluoropyridin-3-yl)methyl)-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole(77.4 mg, 0.140 mmol) and4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1-H-1,2,3-triazole (98.0 mg,0.252 mmol) in DMF (1.0 mL) was added Et₃N (0.0430 mL, 0.308 mmol), andthe mixture was purged with nitrogen. While purging, copper (I) iodide(4.00 mg, 0.0210 mmol) and tetrakis(triphenylphosphine) palladium (0)(19.4 mg, 0.0170 mmol) were added. The reaction mixture was purged withnitrogen for another 5 min and then heated at 95° C. for 2 h. Themixture was cooled to room temperature and diluted with 10% aq. LiClsolution. The mixture was extracted with EtOAc. Combined EtOAc extractswere washed with brine, dried (MgSO₄), filtered, and concentrated togive the crude mixture. The crude product was then purified by silicagel column chromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=DCM/10% MeOH in DCM, RediSep SiO₂ 24 g, detecting at 254 nM, andmonitoring at 220 nM). Concentration of appropriate fractions providedracemic2-[(4,4-difluorocyclohexyl)({7-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine(125 mg). This racemic mixture was separated by chiral prep SFC (BergerSFC MGII, Column: Chiral AD-H 25×3 cm ID, 5 μm Flow rate: 85.0 mL/min,Mobile Phase: 85/15 CO₂/MeOH Detector Wavelength: 220 nm) to giveEnantiomers A (11.8 mg, 14%) and B (12.6 mg, 15%). Enantiomer A: ¹H NMR(400 MHz, CDCl₃) δ 8.59 (d, J=1.7 Hz, 2H), 8.56 (s, 1H), 8.53 (br d,J=3.9 Hz, 1H), 7.93 (dd, J=8.3, 1.3 Hz, 1H), 7.46-7.39 (m, 1H),7.37-7.31 (m, 2H), 5.89 (br d, J=10.6 Hz, 1H), 4.07 (s, 3H), 3.20 (s,3H), 2.15 (br s, 1H), 1.99-1.91 (m, 1H), 1.86 (br s, 1H), 1.55-1.44 (m,1H), 1.39-1.24 (m, 2H), 1.12 (br d, J=12.6 Hz, 1H), 1.03-0.94 (m, 2H);LCMS (M+H)=572.3, SFC RT=7.453 min (Column: Chiralcel AD 250×4.6 mm, 5μm; Mobile Phase: 85/15 CO₂/MeOH; Flow: 2 mL/min); Enantiomer B: ¹H NMR(400 MHz, CDCl₃) δ 8.59 (d, J=1.7 Hz, 2H), 8.57 (d, J=8.2 Hz, 1H), 8.53(br d, J=3.9 Hz, 1H), 7.93 (dd, J=8.2, 1.2 Hz, 1H), 7.46-7.39 (m, 1H),7.37-7.31 (m, 2H), 5.89 (br d, J=10.8 Hz, 1H), 4.07 (s, 3H), 3.20 (s,3H), 2.15 (br s, 1H), 1.95 (br d, J=13.3 Hz, 1H), 1.88 (br d, J=14.8 Hz,1H), 1.55-1.44 (m, 1H), 1.42-1.22 (m, 2H), 1.12 (br d, J=12.1 Hz, 1H).LCMS (M+H)=572.3; SFC RT=8.218 min (Column: Chiralcel AD 250×4.6 mm, 5μm; Mobile Phase: 85/15 CO₂/MeOH; Flow: 2 mL/min).

Example 2433-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]oxetan-3-ol

Step 1: ((3-(4-Bromophenyl)oxetan-3-yl)oxy)(tert-butyl)dimethylsilane

To a stirred reaction solution of 3-(4-bromophenyl)oxetan-3-ol (6.24 g,27.2 mmol; WO2011/159760; (2011); (A1)), tert-butylchlorodimethylsilane(7.39 g, 49.0 mmol) and imidazole (3.71 g, 54.5 mmol) in DMF (50.0 mL)was added 4-dimethylaminopyridine (3.33 g, 27.2 mmol). The mixture wasstirred at room temperature for 67 h and then diluted with ether. Theresulting mixture was washed with 10% aq. LiCl solution and brine. Theorganic layer was dried (MgSO₄), filtered, and concentrated to give thecrude mixture. The crude product was purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=hexane/EtOAc, RediSep SiO₂ 120 g, detecting at 254 nM, andmonitoring at 220 nM). Concentration of appropriate fractions provided((3-(4-bromophenyl)oxetan-3-yl)oxy)(tert-butyl)dimethylsilane (7.11 g,76%). ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.44 (m, 4H), 5.04-4.95 (m, 2H),4.80-4.72 (m, 2H), 0.96 (s, 9H), 0.04 (s, 6H); HPLC: RT=1.27 min(Chromolith ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOHover 4 min containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).

Step 2:tert-Butyldimethyl((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)oxy)silane

To a stirred solution of((3-(4-bromophenyl)oxetan-3-yl)oxy)(tert-butyl)dimethylsilane (100 mg,0.291 mmol) under nitrogen in THF (2.00 mL) at −78° C. was added slowlynBuLi (2.5 M in hexanes, 0.128 mL, 0.320 mmol). The mixture was stirredat −78° C. for 15 min, at which time4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (74.0 mg,0.291 mmol) was added. The mixture was warmed to room temperature andstirred for 16 h. The mixture was then quenched with saturated aq. NH₄Clsolution and extracted with EtOAc. Combined EtOAc extracts were washedwith brine, dried (MgSO₄), filtered, and concentrated to givetert-butyldimethyl((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)oxy)silane(105 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=8.3 Hz, 2H),7.27-7.24 (m, 2H), 4.87-4.84 (m, 2H), 4.73-4.68 (m, 2H), 1.23 (s, 9H),1.14 (s, 12H), 0.82 (s, 6H); HPLC: RT=3.875 min (Chromolith ODS 4.6×50mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 min containing0.1% TFA, 4 mL/min, monitoring at 220 nm).

Step 3:5-Bromo-2-(4-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)phenyl)-3-nitropyridine

tert-Butyldimethyl((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)oxy)silane(1.25 g, 3.20 mmol) and 2,5-dibromo-3-nitropyridine (0.990 g, 3.51 mmol)were combined in dioxane (15 mL) under nitrogen. To this mixture wasadded 2 M aq. tripotassium phosphate (4.80 mL, 9.61 mmol), and it waspurged with nitrogen. While purging, PdCl₂(dppf)-CH₂Cl₂ adduct (0.392 g,0.480 mmol) was added. The mixture was heated at 85° C. for 3 h. Themixture was concentrated, diluted with water, and extracted with EtOAc.Combined EtOAc extracts were washed with brine, dried (MgSO₄), filtered,and concentrated to give the crude product. The crude product waspurified by silica gel column chromatography (Teledyne ISCO CombiFlash0% to 100% solvent A/B=hexane/EtOAc, RediSep SiO₂ 80 g, detecting at 254nM, and monitoring at 220 nM). Concentration of appropriate fractionsprovided5-bromo-2-(4-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)phenyl)-3-nitropyridine(0.570 g, 38%). ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=2.1 Hz, 1H), 8.30(d, J=2.1 Hz, 1H), 7.77-7.69 (m, 2H), 7.60 (d, J=8.6 Hz, 2H), 5.03 (d,J=7.1 Hz, 2H), 4.84 (d, J=7.2 Hz, 2H), 0.98 (s, 9H), 0.08 (s, 6H); HPLC:RT=3.711 min (Chromolith ODS 4.6×50 mm (4 min grad) eluting with 10-90%aqueous MeOH over 4 min containing 0.1% TFA, 4 mL/min, monitoring at 220nm); MS (ES): m/z=465; 467.1 (Br pattern) [M+H]⁺.

Step 4:3-Bromo-7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5H-pyrido[3,2-b]indole

5-Bromo-2-(4-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)phenyl)-3-nitropyridine(1.67 g, 3.59 mmol) and 1,2-bis(diphenylphosphino)ethane (1.79 g, 4.49mmol) were combined in 1,2-dichlorobenzene (35.0 mL) under nitrogen. Themixture was heated at 160° C. for 2 h and cooled to room temperature.The mixture was directly purified by silica gel column chromatography(Teledyne ISCO CombiFlash 0% to 100% solvent A/B=DCM/EtOAc, RediSep SiO₂120 g, detecting at 254 nM, and monitoring at 220 nM). Concentration ofappropriate fractions provided3-bromo-7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5H-pyrido[3,2-b]indole(1.03 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=2.0 Hz, 1H), 8.35(d, J=8.3 Hz, 1H), 8.17 (br. s., 1H), 7.90 (d, J=2.0 Hz, 1H), 7.70 (d,J=0.9 Hz, 1H), 7.64 (dd, J=8.3, 1.5 Hz, 1H), 5.08 (d, J=7.1 Hz, 2H),4.92 (d, J=7.1 Hz, 2H), 0.99 (s, 9H), 0.01 (s, 6H); HPLC: RT=3.416 min(Chromolith ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOHover 4 min containing 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=433.1; 435.1 (Br pattern) [M+H]⁺.

Step 5:7-(3-((tert-Butyldimethylsilyl)oxy)oxetan-3-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole

A stirred mixture of3-bromo-7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5H-pyrido[3,2-b]indole(503 mg, 1.16 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole(896 mg, 2.32 mmol), and Et₃N (0.485 mL, 3.48 mmol) in DMF (8.00 mL) waspurged with nitrogen. While purging, the mixture was treated withcopper(I) iodide (33.2 mg, 0.174 mmol) and Pd(Ph₃P)₄ (134 mg, 0.116mmol), and the reaction mixture was then heated at 95° C. overnight. Thecooled mixture was diluted with EtOAc and washed with 10% aq. LiClsolution and brine. The organic layer was dried (MgSO₄), filtered, andconcentrated. The crude product was purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 100%; followed by 100%flash, solvent A/B=hexane/EtOAc, RediSep SiO₂ 24 g, detecting at 254 nM,and monitoring at 220 nM). Concentration of appropriate fractionsprovided7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole(450 mg, 86%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.53 (d, J=2.0Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.77 (s, 1H),7.50 (dd, J=8.3, 1.5 Hz, 1H), 4.92 (s, 4H), 4.01 (s, 3H), 2.30 (s, 3H),0.92 (s, 9H), −0.05 (s, 6H); HPLC: RT=3.048 min (Chromolith ODS 4.6×50mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 min containing0.1% TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z=450.2 [M+H]⁺.

Step 6:(S)-7-(3-((tert-Butyldimethylsilyl)oxy)oxetan-3-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

To a stirred solution of7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole(100 mg, 0.222 mmol) and((R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (94.0 mg, 0.445mmol) in toluene (1.50 mL) in a cold water bath was addedtriphenylphosphine (117 mg, 0.445 mmol) and DIAD (0.0860 mL, 0.445mmol). The mixture was stirred at room temperature for 4 h, at whichtime another batch of(R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (94.0 mg, 0.445mmol), triphenylphosphine (117 mg, 0.445 mmol), and DIAD (0.0860 mL,0.445 mmol) were added. The mixture was stirred at room temperature for15 h. The mixture was concentrated and purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=DCM/EtOAc, RediSep SiO₂ 24 g, detecting at 254 nM, and monitoring at220 nM). Concentration of appropriate fractions provided(S)-7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(81.0 mg, 57%). HPLC: RT=3.578 min (Chromolith ODS 4.6×50 mm (4 mingrad) eluting with 10-90% aqueous MeOH over 4 min containing 0.1% TFA, 4mL/min, monitoring at 220 nm); MS (ES): m/z=642.3 [M+H]⁺.

Step 7:3-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]oxetan-3-ol

To a stirred solution of(S)-7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(81.0 mg, 0.126 mmol) in THF (4.00 mL) was added 1M TBAF in THF (1.20mL, 1.20 mmol). The mixture was stirred at room temperature for 10 minand concentrated. The crude product was dissolved in DMF and purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge Phenyl, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-70% B over20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give3-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]oxetan-3-ol(33.6 mg, 51%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.27 (d, J=8.1Hz, 1H), 8.20 (br s, 1H), 7.93 (s, 1H), 7.71-7.66 (m, 3H), 7.59 (d,J=8.1 Hz, 1H), 7.15 (br t, J=8.6 Hz, 2H), 5.86 (br d, J=11.1 Hz, 1H),4.88 (br s, 4H), 4.00 (br s, 3H), 3.88 (br d, J=9.4 Hz, 1H), 3.71 (br d,J=8.4 Hz, 1H), 3.47-3.41 (m, 1H), 3.23 (br t, J=11.3 Hz, 1H), 3.17-3.09(m, 1H), 2.28 (s, 3H), 1.67 (br d, J=11.4 Hz, 1H), 1.56 (br d, J=8.8 Hz,2H), 0.97 (br d, J=12.1 Hz, 1H).). LCMS: RT=1.30 min; (ES): m/z(M+H)⁺=528.2, LCMS: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min,then a 0.75-min hold at 100% B; Flow: 1.11 mL/min. HPLC Purity at 220nm: 100%.

Example 2443-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]oxetan-3-ol

Step 1:4-(7-(3-((tert-Butyldimethylsilyl)oxy)oxetan-3-yl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethylisoxazole

To a stirred solution of3-bromo-7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5H-pyrido[3,2-b]indole(418 mg, 0.964 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (272mg, 1.93 mmol) in THF (8.0 mL) was added tripotassium phosphate (2M inH₂O, 1.21 mL, 2.41 mmol). The reaction was degassed with bubblingnitrogen, then PdCl₂(dppf)-CH₂Cl₂ adduct (65.3 mg, 0.0800 mmol) wasadded and the reaction mixture was heated at 85° C. for 55 min. Thecooled mixture was diluted with water and extracted with EtOAc. CombinedEtOAc extracts were dried (MgSO₄), filtered, and concentrated to givethe crude mixture. The crude product was purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=DCM/EtOAc, RediSep SiO₂ 24 g, detecting at 254 nM, and monitoring at220 nM). Concentration of appropriate fractions provided4-(7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethylisoxazole(254 mg, 59%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H), 8.48 (d, J=1.8Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.0Hz, 1H), 7.49 (dd, J=8.2, 1.5 Hz, 1H), 4.94 (s, 4H), 2.50 (s, 3H), 2.32(s, 3H), 0.94 (s, 9H), −0.04 (s, 6H). HPLC: RT=2.983 min (Chromolith ODS4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 mincontaining 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z=450.2[M+H]⁺.

Step 2:(S)-4-(7-(3-((tert-Butyldimethylsilyl)oxy)oxetan-3-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethylisoxazole

To a stirred solution of4-(7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethylisoxazole(250 mg, 0.556 mmol) and ((R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(214 mg, 1.11 mmol) in toluene (4.50 mL) in a cold water bath was addedtriphenylphosphine (292 mg, 1.11 mmol) and DIAD (0.216 mL, 1.11 mmol).The mixture was stirred at room temperature for 2 h, at which timeanother batch of (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (214 mg,1.11 mmol), triphenylphosphine (292 mg, 1.11 mmol), and DIAD (0.216 mL,1.112 mmol) were added. The mixture was stirred at room temperature for14 h. The mixture was concentrated and purified by silica gel columnchromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=DCM/EtOAc, RediSep SiO₂ 24 g, detecting at 254 nM, and monitoring at220 nM). Concentration of appropriate fractions provided(S)-4-(7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethylisoxazole(400 mg, 0.641 mmol, 115%). HPLC: RT=3.573 min (Chromolith ODS 4.6×50 mm(4 min grad) eluting with 10-90% aqueous MeOH over 4 min containing 0.1%TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z=624.3 [M+H]⁺.

Step 3:3-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]oxetan-3-ol

To a stirred solution of(S)-4-(7-(3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-3,5-dimethylisoxazole(410 mg, 0.657 mmol) in THF (7.00 mL) was added 1M TBAF in THF (3.20 mL,3.20 mmol). The mixture was stirred at room temperature for 15 min andconcentrated. The crude product was dissolved in DMF and purified viapreparative LC/MS with the following conditions: Column: Waters XBridgePhenyl, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-70% B over20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give3-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]oxetan-3-ol(16.5 mg, 5%) ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.27 (br d,J=8.4 Hz, 3H), 7.68 (br d, J=7.4 Hz, 2H), 7.61 (br d, J=8.1 Hz, 1H),7.36 (br t, J=7.4 Hz, 2H), 7.31-7.23 (m, 1H), 6.59 (s, 1H), 5.88 (br d,J=11.1 Hz, 1H), 4.91 (br s, 4H), 3.97-3.89 (m, 1H), 3.76 (br d, J=8.4Hz, 1H), 3.52 (br d, J=10.8 Hz, 1H), 3.42 (br s, 1H), 3.28 (br t, J=11.3Hz, 1H), 2.54 (br s, 3H), 2.33 (br s, 3H), 1.76 (br d, J=12.5 Hz, 1H),1.62 (br d, J=9.8 Hz, 1H), 1.35 (br d, J=8.8 Hz, 1H), 1.00 (br d, J=13.1Hz, 1H). LCMS: RT=1.29 min; (ES): m/z (M+H)⁺=510.2. LCMS: Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min. HPLC Purity at 220 nm: 96%.

Examples 245 & 2462-{[9-(2,2-Difluoroethoxy)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl](oxan-4-yl)methyl}-3-fluoropyridine

Step 1:3-Bromo-9-(2,2-difluoroethoxy)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole

To a stirred reaction mixture of3-bromo-9-fluoro-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole (50.0 mg,0.146 mmol) and 2,2-difluoroethanol (120 mg, 1.46 mmol) in NMP (0.50 mL)was added t-BuOK (131 mg, 1.17 mmol). The mixture was heated at 65° C.for 17 h. The cooled mixture was diluted with EtOAc and washed withbrine. The EtOAc layer was dried (MgSO₄), filtered, and concentrated togive the crude mixture. The crude product was purified by silica gelcolumn chromatography (Teledyne ISCO CombiFlash 0% to 100% solventA/B=DCM/10% MeOH in DCM, RediSep SiO₂ 12 g, detecting at 254 nM, andmonitoring at 220 nM). Concentration of appropriate fractions provided3-bromo-9-(2,2-difluoroethoxy)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(64.0 mg, 108%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (br s, 1H), 8.65 (d,J=2.1 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.95 (s, 1H), 7.13 (d, J=8.7 Hz,1H), 4.72 (td, J=14.4, 3.7 Hz, 2H), 3.33-3.32 (m, 1H), 2.69 (s, 3H).HPLC: RT=2.067 min (Chromolith ODS 4.6×50 mm (4 min grad) eluting with10-90% aqueous MeOH over 4 min containing 0.1% TFA, 4 mL/min, monitoringat 220 nm); MS (ES): m/z=405.1; 407 (Br pattern) [M+H]⁺.

Step 2:5-[9-(2,2-Difluoroethoxy)-6-methanesulfonyl-5Hpyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

A stirred solution of3-bromo-9-(2,2-difluoroethoxy)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(62.3 mg, 0.154 mmol) and4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1-H-1,2,3-triazole (108 mg,0.277 mmol) in DMF (0.80 mL) and Et₃N (0.0470 mL, 0.338 mmol) was purgedwith nitrogen. While purging with nitrogen, to this mixture was addedPd(PPh₃)₄ (21.3 mg, 0.0180 mmol) and copper (I) iodide (4.39 mg, 0.0230mmol). The reaction mixture was heated at 95° C. for 5 h. The cooledmixture was diluted with 10% aq. LiCl solution and extracted with EtOAc.Combined EtOAc extracts were washed with brine, dried (MgSO₄), filtered,and concentrated to give the crude mixture. The crude product waspurified by silica gel column chromatography (Teledyne ISCO CombiFlash0% to 100% solvent A/B=DCM/10% MeOH in DCM, RediSep SiO₂ 12 g, detectingat 254 nM, and monitoring at 220 nM). Concentration of appropriatefractions provided5-[9-(2,2-difluoroethoxy)-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(24.3 mg, 37%). ¹H NMR (400 MHz, CD₃OD) δ 8.58 (d, J=2.0 Hz, 1H), 8.07(d, J=8.7 Hz, 2H), 8.02 (d, J=2.0 Hz, 1H), 7.00 (s, 1H), 4.68 (td,J=13.0, 4.2 Hz, 3H), 4.06 (s, 3H), 3.25 (s, 3H). HPLC: RT=1.750 min(Chromolith ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOHover 4 min containing 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=425.2 [M+H]⁺.

Step 3:2-{[9-(2,2-Difluoroethoxy)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl](oxan-4-yl)methyl}-3-fluoropyridine

5-[9-(2,2-Difluoroethoxy)-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(22.0 mg, 0.0520 mmol) and(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (21.9 mg, 0.104mmol) were combined in Toluene (0.50) in a cold water bath. To thismixture was added triphenylphosphine (27.2 mg, 0.104 mmol) and DIAD(0.0200 mL, 0.104 mmol). The mixture was stirred at room temperature for4.5 h and purified by silica gel column chromatography (Teledyne ISCOCombiFlash 0% to 100% solvent A/B=DCM/10% MeOH in DCM, RediSep SiO₂ 12g, detecting at 254 nM, and monitoring at 220 nM). Concentration ofappropriate fractions provided racemic2-{[9-(2,2-difluoroethoxy)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl](oxan-4-yl)methyl}-3-fluoropyridine(105 mg). This racemic mixture was separated by chiral prep SFC (BergerSFC MGII, Column: Chiral IB 25×2.1 cm ID, 5 μm Flow rate: 50.0 mL/min.Mobile Phase: 78/22 CO₂/MeOH Detector Wavelength: 220 nm) to giveEnantiomers A (1.10 mg, 3%) and B (1.00 mg, 3%). Enantiomer A: ¹H NMR(500 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.51 (br d, J=4.4 Hz, 1H), 8.30 (d,J=9.0 Hz, 1H), 8.07 (s, 1H), 7.63 (br t, J=9.5 Hz, 1H), 7.46 (dt, J=8.3,4.2 Hz, 1H), 7.23 (d, J=8.9 Hz, 1H), 6.96 (br d, J=10.2 Hz, 1H),6.69-6.42 (m, 1H), 4.73 (td, J=14.3, 3.2 Hz, 2H), 3.89 (s, 3H), 3.83 (brd, J=10.9 Hz, 1H), 3.62 (br d, J=7.8 Hz, 1H), 3.58-3.53 (m, 1H),3.36-3.28 (m, 1H), 3.12 (br t, J=11.7 Hz, 1H), 2.54 (s, 3H), 1.79-1.64(m, 2H), 1.63-1.51 (m, 1H), 0.42 (br d, J=12.2 Hz, 1H). LCMS(M+H)=618.3; SFC RT=5.019 min (Column: Chiralcel IB 250×4.6 mm, 5 μm;Mobile Phase: 70/30 CO₂/MeOH; Flow: 2 mL/min); Enantiomer B: ¹H NMR (500MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.52 (br d, J=4.5 Hz, 1H), 8.30 (d, J=8.9Hz, 1H), 8.08 (s, 1H), 7.68-7.57 (m, 1H), 7.52-7.41 (m, 1H), 7.24 (d,J=9.0 Hz, 1H), 6.96 (br d, J=10.1 Hz, 1H), 6.71-6.38 (m, 1H), 4.74 (td,J=14.3, 3.2 Hz, 2H), 3.93-3.88 (m, 3H), 3.84 (br d, J=9.8 Hz, 1H), 3.63(br d, J=9.2 Hz, 1H), 3.54 (s, 1H), 3.36-3.26 (m, 1H), 3.12 (br t,J=11.7 Hz, 1H), 2.54 (s, 3H), 1.79-1.65 (m, 2H), 1.63-1.50 (m, 1H), 0.42(br d, J=12.0 Hz, 1H). LCMS (M+H)=618.3. SFC RT=6.211 min (Column:Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/MeOH; Flow: 2mL/min).

Examples 247 & 2482-{[9-(2,2-Difluoropropoxy)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl](oxan-4-yl)methyl}-3-fluoropyridine

Step 1:3-Bromo-9-(2,2-difluoroethoxy)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole

To a stirred reaction mixture of3-bromo-9-fluoro-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole (50.0 mg,0.146 mmol) and 2,2-difluoropropan-1-ol (140 mg, 1.46 mmol) in NMP (0.50mL) was added t-BuOK (131 mg, 1.17 mmol). The mixture was heated at 65°C. for 2 h. The cooled mixture was diluted with EtOAc and washed withwater and brine. The EtOAc layer was dried (MgSO₄), filtered, andconcentrated to give the crude mixture. The crude product was purifiedby silica gel column chromatography (Teledyne ISCO CombiFlash 0% to 100%solvent A/B=DCM/10% MeOH in DCM, RediSep SiO₂ 12 g, detecting at 254 nM,and monitoring at 220 nM). Concentration of appropriate fractionsprovided3-bromo-9-(2,2-difluoroethoxy)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(61.0 mg, 100%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (br s, 1H), 8.64 (d,J=2.1 Hz, 1H), 8.24 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.12 (d, J=8.7 Hz,1H), 4.67 (t, J=12.2 Hz, 2H), 3.32-3.27 (m, 3H), 2.69 (s, 3H). HPLC:RT=2.392 min (Chromolith ODS 4.6×50 mm (4 min grad) eluting with 10-90%aqueous MeOH over 4 min containing 0.1% TFA, 4 mL/min, monitoring at 220nm); MS (ES): m/z=419; 421 (Br pattern) [M+H]⁺.

Step 25-[9-(2,2-Difluoropropoxy)-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

A stirred solution of3-bromo-9-(2,2-difluoropropoxy)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(60.3 mg, 0.144 mmol) and4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1-H-1,2,3-triazole (101 mg,0.259 mmol) in DMF (0.80 mL) and Et₃N (0.044 mL, 0.316 mmol) was purgedwith nitrogen. While purging with nitrogen, to this mixture was addedPd(PPh₃)₄ (19.9 mg, 0.0170 mmol) and copper (I) iodide (4.11 mg, 0.0220mmol). The reaction mixture was heated at 95° C. for 1.5 h. The cooledmixture was diluted with 10% aq. LiCl solution and extracted with EtOAc.Combined EtOAc extracts were washed with brine, dried (MgSO₄), filtered,and concentrated to give the crude mixture. The crude product waspurified by silica gel column chromatography (Teledyne ISCO CombiFlash0% to 100% solvent A/B=DCM/10% MeOH in DCM, RediSep SiO₂ 12 g, detectingat 254 nM, and monitoring at 220 nM). Concentration of appropriatefractions provided5-[9-(2,2-difluoropropoxy)-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(40.0 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 8.68 (d,J=2.0 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.14 (d,J=8.7 Hz, 1H), 4.70 (t, J=12.1 Hz, 2H), 4.01 (s, 3H), 3.34 (s, 3H),2.04-1.90 (m, 3H). HPLC: RT=1.995 min (Chromolith ODS 4.6×50 mm (4 mingrad) eluting with 10-90% aqueous MeOH over 4 min containing 0.1% TFA, 4mL/min, monitoring at 220 nm); MS (ES): m/z=439.2 [M+H]⁺.

Step 3:2-{[9-(2,2-Difluoropropoxy)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl](oxan-4-yl)methyl}-3-fluoropyridine

5-[9-(2,2-Difluoropropoxy)-6-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl]-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(38.0 mg, 0.0870 mmol) and(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol (36.6 mg, 0.173mmol) were stirred in toluene (1.00 mL) in a cold water bath. To thismixture was added triphenylphosphine (45.5 mg, 0.173 mmol) and DIAD(0.0340 mL, 0.173 mmol). The mixture was stirred at room temperature for4.5 h and purified by silica gel column chromatography (Teledyne ISCOCombiFlash 0% to 100% solvent A/B=DCM/10% MeOH in DCM, RediSep SiO₂ 12g, detecting at 254 nM, and monitoring at 220 nM). Concentration ofappropriate fractions provided racemic2-{[9-(2,2-difluoropropoxy)-6-methanesulfonyl-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl](oxan-4-yl)methyl}-3-fluoropyridine(164 mg). This racemic mixture was separated by chiral prep SFC (BergerSFC MGII, Column: Chiral IB 25×2.1 cm IB, 5 μm Flow rate: 50.0 mL/min.Mobile Phase: 78/22 CO₂/MeOH Detector Wavelength: 220 nm) to giveEnantiomers A (4.30 mg, 8%) and B (4.30 mg, 8%). Enantiomer A: ¹H NMR(500 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.52 (br d, J=4.4 Hz, 1H), 8.30 (d,J=8.8 Hz, 1H), 8.04 (s, 1H), 7.63 (br t, J=9.6 Hz, 1H), 7.47 (dt, J=8.3,4.2 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 6.98 (br d, J=10.2 Hz, 1H), 4.68(br t, J=11.9 Hz, 2H), 3.89 (s, 3H), 3.84 (br d, J=9.4 Hz, 1H), 3.63 (brd, J=8.3 Hz, 1H), 3.56-3.50 (m, 1H), 3.34 (br t, J=10.9 Hz, 1H), 3.13(br t, J=11.3 Hz, 1H), 2.54 (s, 3H), 1.97 (br t, J=19.4 Hz, 3H),1.80-1.66 (m, 2H), 1.64-1.52 (m, 1H), 0.44 (br d, J=11.8 Hz, 1H) LCMS(M+H)=632.3; SFC RT=6.376 min (Column: Chiralcel IB 250×4.6 mm, 5 μm;Mobile Phase: 75/25 CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ¹H NMR (500MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.52 (br d, J=4.5 Hz, 1H), 8.30 (d, J=8.9Hz, 1H), 8.04 (s, 1H), 7.63 (br t, J=9.6 Hz, 1H), 7.47 (dt, J=8.3, 4.2Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 6.98 (br d, J=10.1 Hz, 1H), 4.68 (br t,J=11.9 Hz, 2H), 3.89 (s, 3H), 3.83 (br s, 1H), 3.63 (br d, J=8.4 Hz,1H), 3.55-3.49 (m, 1H), 3.37-3.27 (m, 1H), 3.13 (br t, J=11.2 Hz, 1H),2.54 (s, 3H), 1.97 (br t, J=19.4 Hz, 3H), 1.80-1.65 (m, 2H), 1.63-1.52(m, 1H), 0.44 (br d, J=11.4 Hz, 1H). LCMS (M+H)=632.2; SFC RT=7.707 min(Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO₂/MeOH;Flow: 2 mL/min).

Examples 249 & 2502-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(4-methoxyphenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: N-Methoxy-N-methyloxane-4-carboxamide

To a 500 mL round bottom flask containing a solution ofoxane-4-carboxylic acid (8.00 g, 61.5 mmol) in CH₂Cl₂ (100 mL),1,1′-carbonyldiimidazole (12.0 g, 73.8 mmol) was added in portions. Thereaction solution was stirred at room temperature for 2 h.N,O-Dimethylhydroxylamine hydrochloride (6.60 g, 67.6 mmol) then wasadded in one portion. The reaction was stirred at room temperature for16 h. The reaction mixture was quenched with saturated aq. ammoniumchloride and separated. The organic layer was washed with saturated aq.NaHCO₃, dried with sodium sulfate, filtered, and concentrated to givethe title compound (9.50 g, 89%), which was used as withoutpurification. ¹H NMR (400 MHz, CD₃OD) δ 3.99 (ddd, J=11.5, 4.2, 2.1 Hz,2H), 3.77 (s, 3H), 3.51 (td, J=11.8, 2.4 Hz, 2H), 1.7 Hz, 1H), 3.21 (s,3H), 3.06 (br. s., 1H), 1.88-1.52 (m, 4H); LCMS (M+H)=174.2; HPLCRT=1.39 min (Column: Waters Sunfire C18, 2.1×50 mm, 3.5-μm particles;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min, then a 1.00 min hold at 100% B; Flow: 4 mL/min; Detection: UV at220 nm).

Step 2: 4-(4-Methoxybenzoyl)oxane

To a 100 mL round bottom flask containing a solution of1-bromo-4-methoxybenzene (3.24 g, 17.3 mmol) in THF (10 mL) cooled to−78° C., 1.6 M nBuLi in hexanes (10.8 mL, 17.3 mmol) was added dropwise.The reaction solution became cloudy and was stirred at −78° C. for 10min, then at room temperature for 10 min to give a clear solution. Thereaction was then cooled back down to −78° C. and treated with asolution of N-methoxy-N-methyloxane-4-carboxamide (1.00 g, 5.77 mmol) in5 mL of THF to give a very dark solution. The solution was stirred at−78° C. for 1 h. The reaction was quenched by pouring it into a mixtureof ice and saturated aq. NH₄Cl and extracting the product into ethylacetate. The organic phase was washed with water and concentrated togive an off-white solid. The crude product mixture was purified usingISCO silica gel chromatography (40 g column, gradient from 0% to 25%EtOAc/DCM in 10 min) to give the title compound (1.02 g, 80%). ¹H NMR(400 MHz, CDCl₃) δ 8.07-7.86 (m, 2H), 7.06-6.91 (m, 2H), 4.15-4.00 (m,2H), 3.94-3.86 (m, 3H), 3.66-3.31 (m, 3H), 2.06-1.69 (m, 4H); LCMS(M+H)=221.0; HPLC RT=0.80 min (Column: Waters Acquity UPLC BEH C18,2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:waterwith 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% Bover 1.5 min, then a 0.2-min hold at 100% B; Flow: 0.8 mL/min;Detection: UV at 220 nm).

Step 3: (4-Methoxyphenyl)(oxan-4-yl)methanol

A 100 mL round bottomed flask was charged with a solution of4-(4-methoxybenzoyl)oxane (1000 mg, 4.54 mmol) in MeOH (10 mL). Thereaction solution was cooled in an ice bath. Solid NaBH₄ (258 mg, 6.81mmol) was added slowly in small batches to the reaction solution. Thereaction was stirred in an ice/water bath for 1 h. The reaction wasquenched with water, and the reaction solution concentrated in vacuo.The solution was acidified with citric acid to pH 4, and extracted withDCM (2×). The organic phase was washed with brine, dried, andconcentrated. The crude product mixture was purified using ISCO silicagel chromatography (40 g column, gradient from 0% to 25% EtOAc/DCM in 15min) to give the title compound (0.910 g, 90%). ¹H NMR (400 MHz, CDCl₃)δ 7.28-7.21 (m, 2H), 7.35-7.17 (m, 7H), 6.91 (d, J=8.8 Hz, 2H),4.48-3.85 (m, 4H), 3.83 (s, 3H), 3.69-3.17 (m, 2H), 1.79 (d, J=2.9 Hz,3H), 1.57-0.97 (m, 14H); LCMS (M-18)=205; HPLC RT=0.70 min (Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile PhaseB: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature:50° C.; Gradient: 0-100% B over 1.5 min, then a 0.2-min hold at 100% B;Flow: 0.8 mL/min; Detection: UV at 220 nm).

Step 4: Methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-methoxyphenyl)(oxan-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a 25 mL round bottomed flask containing a solution of methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(85.0 mg, 0.265 mmol) and 4-methoxyphenyl)(oxan-4-yl)methanol (118 mg,0.529 mmol) in DCM (10 mL) at 0° C. was added solid triphenylphosphine(139 mg, 0.529 mmol) and DIAD (0.103 mL, 0.529 mmol). The resultingsuspension was stirred at room temperature overnight and thenconcentrated. The crude product mixture was purified using ISCO silicagel chromatography (40 g column, gradient from 0% to 100% EtOAc/CH₂Cl₂in 15 min) to give the title compound (75.0 mg, 54%). LCMS (M+H)=526;HPLC RT=0.93 min (Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 1.5min, then a 0.2-min hold at 100% B; Flow: 0.8 mL/min; Detection: UV at220 nm).

Step 5:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(4-methoxyphenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

A 25 mL round-bottomed flask containing methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-methoxyphenyl)(oxan-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(75.0 mg, 0.143 mmol) in THF (8 mL) was cooled in an ice/MeOH bath. Asolution of methylmagnesium bromide (3M in Et₂O, 0.381 mL, 1.14 mmol)was added slowly dropwise. The reaction was stirred in the ice/MeOH bathfor 15 min then let warm to room temperature for 10 min. The reactionwas re-cooled in an ice/MeOH bath, and another portion ofmethylmagnesium bromide (3M in Et₂O, 0.381 mL, 1.14 mmol) was added.After 15 min, the reaction was warmed to room temperature for 10 min.The reaction was re-cooled in the ice/MeOH bath and quenched withsaturated aq. NH₄Cl solution and diluted with 10% aq. LiCl solution. Theaqueous layer was extracted with CHCl₃ (2×), and the organic layer wasdried over Na₂SO₄, filtered, and concentrated. The crude product mixturewas purified using ISCO silica gel chromatography (24 g column, gradientfrom 0% to 100% EtOAc/CH₂Cl₂ in 15 min) to give the racemic titlecompound, which was separated using chiral prep SFC (Column: ChiralpakIB, 25×2 cm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH; Flow: 50 mL/min). Thefaster eluting peak was assigned as Enantiomer A (16.0 mg, 20%). ¹H NMR(400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.22 (s, 1H),8.13 (s, 1H), 7.59-7.38 (m, 3H), 6.90 (d, J=8.6 Hz, 2H), 5.73 (d, J=11.0Hz, 1H), 4.08-3.94 (m, 4H), 3.82 (dd, J=11.3, 3.0 Hz, 1H), 3.74 (s, 2H),3.65-3.49 (m, 1H), 3.48-3.35 (m, 1H), 2.44-2.23 (m, 2H), 1.98 (d, J=13.2Hz, 1H), 1.81-1.50 (m, 7H), 1.51-1.02 (m, 3H LCMS (M+H)=526.5; HPLCRT=8.08 min (Column: Sunfire C18 3.5 μm, 3.0×150 mm; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient 0-100% B over 15 min; Flow:1.0 mL/min; Detection: UV at 220 nm); Chiral HPLC RT=8.778 min (Column:Chiralpak IB, 250×4.6 mm, Sum particle; Mobile Phase: 75/25 CO₂/MeOH;Flow rate: 2.0 mL/min; Detection: UV at 220 nm). The slower eluting peakwas assigned as Enantiomer B (14.3 mg, 19%). ¹H NMR (500 MHz, DMSO-d₆) δ8.56-8.22 (m, 1H), 8.22-8.01 (m, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.46 (d,J=8.1 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 5.73 (d, J=11.1 Hz, 1H), 4.00(br. s., 2H), 3.89 (d, J=9.1 Hz, 1H), 3.72 (d, J=8.8 Hz, 1H), 3.67-3.54(m, 2H), 3.46 (t, J=11.4 Hz, 1H), 3.39-3.15 (m, 2H), 2.29 (s, 3H), 1.70(d, J=12.5 Hz, 1H), 1.65-1.40 (m, 6H), 1.30 (d, J=9.1 Hz, 1H), 0.99 (d,J=11.4 Hz, 1H) LCMS (M+H)=526.5; HPLC RT=1.608 min Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min; Detection: UV at 220 nm; Chiral HPLC RT=12.020 min (Column:Chiralpak IB, 250×4.6 mm, 5 μm particle; Mobile Phase: 75/25 CO₂/MeOH;Flow rate: 2.0 mL/min; Detection: UV at 220 nm).

Example 2512-{5-[Cyclobutyl(4-fluorophenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Cyclobutyl(4-fluorophenyl)methanol

A mixture of magnesium (0.783 g, 32.2 mmol), bromocyclobutane (4.35 g,32.2 mmol), and 2 drops of dibromoethane in THF (40.3 ml) was sonicatedfor 2 min and then refluxed for 1 h. The mixture was cooled to 0° C.followed by a slow addition of a solution of 4-fluorobenzaldehyde (2.00g, 16.1 mmol) in THF (5 mL). The reaction was stirred at 0° C. for 2 h.The reaction was quenched with NH₄Cl, and the mixture was extracted withEtOAc (3×). The organic layer was separated, concentrated, and theresidue was purified by silica gel chromatography (40 g column, gradientfrom 0% to 50% EtOAc/hexanes) to give the title compound (1.50 g, 52%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.30 (dd, J=8.6, 5.7 Hz,2H), 7.03 (t, J=8.7 Hz, 2H), 4.58 (dd, J=7.9, 3.3 Hz, 1H), 2.72-2.53 (m,1H), 2.17-2.07 (m, 1H), 2.05-1.95 (m, 1H), 1.91 (d, J=3.3 Hz, 1H),1.89-1.75 (m, 4H); LCMS (M+H—H₂O)=163.1; HPLC RT=0.87 min (Column: BEHC18 2.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min).

Step 2:2-{5-[Cyclobutyl(4-fluorophenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 of2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(75.0 mg, 0.230 mmol) and cyclobutyl(4-fluorophenyl)methanol (84.0 mg,0.480 mmol) were converted to racemic2-{5-[cyclobutyl(4-fluorophenyl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep SFC to give the title compound (15.0mg, 19%). ¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J=1.6 Hz, 1H), 8.33 (d,J=8.3 Hz, 1H), 7.94 (br. s., 2H), 7.53-7.48 (m, 2H), 7.38-7.32 (m, 3H),7.07 (t, J=8.7 Hz, 2H), 6.13 (d, J=11.0 Hz, 1H), 3.96 (s, 3H), 3.70 (s,2H), 3.66 (s, 2H), 2.28 (s, 3H), 2.08-1.98 (m, 2H), 1.86-1.76 (m, 2H),1.65 (d, J=1.7 Hz, 6H); LCMS (M+H)=484.5; HPLC RT=0.85 min (Column: BEHC18 2.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min); SFC RT=13.03 min (Column: Chiralcel OJ-H 250×4.6 mm, 5 μm;Mobile Phase: 89/11 CO₂/MeOH; Flow: 2 mL/min).

Example 2521-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-2-methylpropan-2-ol

Step 1: Ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

A suspension of ethyl 2-(4-bromophenyl)acetate (500 mg, 2.06 mmol),bis(pinacolato)diboron (1.05 mg, 4.11 mmol), and potassium acetate (606mg, 6.17 mmol) in dioxane (4 mL) was degassed with bubbling nitrogen.PdCl₂(dppf)-CH₂Cl₂ adduct (84.0 mg, 0.100 mmol) was added, and thereaction was heated to 85° C. for 4 h. The reaction was diluted withethyl acetate (30 mL) and filtered through Celite. The organic layer waswashed with brine, separated, and dried with sodium sulfate. The solventwas evaporated, and the residue was purified by column chromatography onsilica gel (40 g column, gradient from 0% to 20% EtOAc/hexanes) to givethe title compound (471 mg, 79%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.79 (d, J=7.9 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 4.16 (q, J=7.1Hz, 2H), 3.64 (s, 2H), 1.36 (s, 12H), 1.26 (t, J=7.2 Hz, 3H); LCMS(M+H)=291.3; HPLC RT=1.03 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Step 2: Ethyl 2-(4-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate

To a solution of ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (460mg, 1.59 mmol) and 2,5-dibromo-3-nitropyridine (447 mg, 1.59 mmol) inTHF (5 mL) was added tripotassium phosphate (2M) (1.50 mL, 3.17 mmol).The reaction was degassed with bubbling nitrogen followed by theaddition of PdCl₂(dppf)-CH₂Cl₂ adduct (64.7 mg, 0.0790 mmol). Thereaction was heated to 70° C. for 4 h. The reaction mixture wastransferred to a reparatory funnel containing saturated aqueous NaHCO₃solution (25 mL). The aqueous layer was extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over MgSO₄, filtered, and concentrated. The residue was purifiedby column chromatography on silica gel (24 g column, gradient from 0% to20% EtOAc/hexanes) to give the title compound (265 mg, 46%) as acolorless oil. LCMS (M+H)=365.2; HPLC RT=0.98 min (Column: BEH C182.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min).

Step 3: Ethyl 2-(3-bromo-5H-pyrido[3,2-b]indol-7-yl)acetate

A solution of ethyl 2-(4-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate(260 mg, 0.710 mmol) and DPPE (355 mg, 0.890 mmol) in o-dichlorobenzene(2.4 mL) was heated to 170° C. for 2 h. The solvent was evaporated, andthe residue was purified by column chromatography on silica gel (24 gcolumn, gradient from 0% to 30% EtOAc/hexanes) to give the titlecompound (155 mg, 65%). ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=2.0 Hz,1H), 8.28 (d, J=8.1 Hz, 1H), 8.10 (br. s., 1H), 7.88 (d, J=2.0 Hz, 1H),7.43 (s, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.30 (t, J=7.1 Hz,3H); LCMS (M+H)=334.9; HPLC RT=0.84 min (Column: BEH C18 2.1×50 mm;Mobile Phase A: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Step 4: Ethyl2-(3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl)acetate

To a suspension of ethyl 2-(3-bromo-5H-pyrido[3,2-b]indol-7-yl)acetate(150 mg, 0.450 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (127mg, 0.900 mmol) in DMF (2 mL), tripotassium phosphate (3M in H₂O) (675μl, 1.35 mmol) was added. The solution was degassed with nitrogen.PdCl₂(dppf) (16.5 mg, 0.0230 mmol) was added, and the mixture was heatedin a pressure vial at 80° C. for 3 h. The reaction mixture wastransferred to a separatory funnel containing saturated aqueous NaHCO₃solution (25 mL). The aqueous layer was extracted with ethyl acetate(3×25 mL). The combined organic layers were washed with brine (25 mL),dried over MgSO₄, filtered, and concentrated. The residue was purifiedby column chromatography on silica gel (24 g column, gradient from 0% to5% MeOH/DCM) to give the title compound (82.0 mg, 52%). ¹H NMR (400 MHz,CDCl₃) δ 8.94 (s, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.26 (d, J=8.1 Hz, 1H),7.56 (d, J=1.7 Hz, 1H), 7.44 (s, 1H), 7.24 (dd, J=8.1, 1.1 Hz, 1H), 4.22(q, J=7.2 Hz, 2H), 3.83 (s, 2H), 2.47 (s, 3H), 2.32 (s, 3H), 1.30 (t,J=7.1 Hz, 3H); LCMS (M+H)=350.3; HPLC RT=0.68 min (Column: BEH C182.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min).

Step 5:1-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-2-methylpropan-2-ol

Following procedures analogous to those described in Steps 4 and 5 of2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,ethyl2-(3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl)acetate(30.0 mg, 0.0900 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(33.0 mg, 0.170 mmol) were converted to the title compound (9.50 mg,47%). ¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J=1.5 Hz, 1H), 8.53 (br. s.,1H), 8.31 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 7.66 (d, J=7.3 Hz, 2H),7.40-7.34 (m, 3H), 7.33-7.27 (m, 1H), 5.86 (d, J=11.0 Hz, 1H), 4.01 (dd,J=11.6, 2.8 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.62 (td, J=11.8,1.9 Hz, 1H), 3.49-3.39 (m, 2H), 3.07 (s, 2H), 2.48 (s, 3H), 2.31 (s,3H), 1.74-1.57 (m, 1H), 1.51-1.38 (m, 1H), 1.27 (d, J=12.2 Hz, 6H), 1.14(d, J=12.7 Hz, 1H); LCMS (M+H)=510.4; HPLC RT=0.81 min (Column: BEH C182.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min).

Examples 253 & 2542-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[4,4,4-trifluoro-1-(pyridin-2-yl)butyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 4,4,4-Trifluoro-1-(pyridin-2-yl)butan-1-ol

To a mixture of magnesium (0.340 g, 14.0 mmol) and dibromoethane (2drops) in THF (23.3 ml), 3-bromo-1,1,1-trifluoropropane (2.45 g, 14.0mmol) was added. The mixture was heated to 60° C. for 40 min. Thereaction was cooled to 0° C. followed by a slow addition ofpicolinaldehyde (1.00 g, 9.34 mmol). The reaction was stirred at 0° C.for 1 h. The reaction was quenched with 2 mL NH₄Cl solution and dilutedwith water. The aqueous layer was extracted with EtOAc (2×). The organiclayer was separated, concentrated, and dried to afford the titlecompound (1.10 g, 57%) as a tan solid. ¹H NMR (400 MHz, CD₃OD) δ8.52-8.42 (m, 1H), 7.86 (td, J=7.8, 1.7 Hz, 1H), 7.63-7.53 (m, 1H), 7.32(ddd, J=7.5, 4.9, 1.0 Hz, 1H), 4.76 (dd, J=8.3, 4.3 Hz, 1H), 2.36-2.19(m, 2H), 2.14-2.00 (m, 1H), 1.96-1.85 (m, 1H); LCMS (M+H)=206.2; HPLCRT=0.49 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with 0.05%TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98% B over1.6 min; Flow: 0.8 mL/min).

Step 2:2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(4,4,4-trifluoro-1-(pyridin-2-yl)butyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 of2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(100 mg, 0.310 mmol) and 4,4,4-trifluoro-1-(pyridin-2-yl)butan-1-ol (128mg, 0.620 mmol) were converted toracemic2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(4,4,4-trifluoro-1-(pyridin-2-yl)butyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol,which was separated by chiral prep SFC to give Enantiomers A and B.Enantiomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.67 (dd, J=4.8, 0.8 Hz, 1H),8.51 (d, J=1.7 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H),7.88 (s, 1H), 7.74 (td, J=7.7, 1.8 Hz, 1H), 7.56 (dd, J=8.4, 1.3 Hz,1H), 7.35 (dd, J=7.2, 5.3 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 6.32 (dd,J=10.0, 5.7 Hz, 1H), 4.01 (s, 3H), 3.17-3.03 (m, 1H), 2.99-2.85 (m, 1H),2.43 (dt, J=14.7, 5.5 Hz, 1H), 2.31 (s, 3H), 1.98-1.80 (m, 1H), 1.64 (s,6H); LCMS (M+H)=509.3; HPLC RT=0.79 min (Column: BEH C18 2.1×50 mm;Mobile Phase A: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min); SFCRT=5.41 (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20CO₂/MeOH; Flow: 2 mL/min). Enantiomer B: ¹H NMR (400 MHz, CD₃OD) δ 8.67(dd, J=4.8, 0.8 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H),8.08 (d, J=1.6 Hz, 1H), 7.88 (s, 1H), 7.74 (td, J=7.8, 1.8 Hz, 1H), 7.56(dd, J=8.4, 1.3 Hz, 1H), 7.35 (dd, J=7.2, 5.3 Hz, 1H), 7.28 (d, J=7.9Hz, 1H), 6.32 (dd, J=10.1, 5.6 Hz, 1H), 4.01 (s, 3H), 3.16-3.04 (m, 1H),2.99-2.85 (m, 1H), 2.42 (s, 1H), 2.31 (s, 3H), 1.97-1.83 (m, 1H), 1.64(s, 6H); LCMS (M+H)=509.4; HPLC RT=0.79 min (Column: BEH C18 2.1×50 mm;Mobile Phase A: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min); SFCRT=6.68 (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 80/20CO₂/MeOH; Flow: 2 mL/min).

Example 2551-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]-2-methylpropan-2-ol

Step 1: Methyl2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

A suspension of methyl 2-(3-bromophenyl)acetate (5.00 g, 21.8 mmol),bis(pinacolato)diboron (11.1 g, 43.7 mmol) and potassium acetate (6.43g, 65.5 mmol) in dioxane (43.7 ml) was degassed with bubbling nitrogen.PdCl₂(dppf)-CH₂Cl₂ adduct (0.446 g, 0.546 mmol) was added, and thereaction was heated to 85° C. for 4 h. The reaction was diluted withethyl acetate (30 mL) and filtered through Celite. The organic layer waswashed with brine, separated, and dried with sodium sulfate. The solventwas evaporated, and the residue was purified by column chromatography onsilica gel (220 g column, gradient from 0% to 40% EtOAc/hexanes) to givethe title compound (6.00 g, 100%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.74 (s, 1H), 7.72 (s, 1H), 7.40 (t, J=1.7 Hz, 1H), 7.38-7.33(m, 1H), 3.70 (s, 3H), 3.65 (s, 2H), 1.36 (s, 12H); LCMS (M+H)=277.3;HPLC RT=0.99 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98%B over 1.6 min; Flow: 0.8 mL/min).

Step 2: Methyl 2-(3-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate

Following a procedure analogous to that described for ethyl2-(4-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate, methyl2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (5.00g, 18.1 mmol) and 2,5-dibromo-3-nitropyridine (5.10 g, 18.1 mmol) wereconverted to the title compound (4.20 g, 66%). ¹H NMR (400 MHz, DMSO-d₆)δ 9.10 (d, J=2.1 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d,J=1.6 Hz, 1H), 7.42-7.41 (m, 1H), 3.78 (s, 2H), 3.64 (s, 3H); LCMS(M+H)=351.1; HPLC RT=0.93 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Step 3: Methyl 2-(3-bromo-5H-pyrido[3,2-b]indol-8-yl)acetate

Following a procedure analogous to that described for ethyl2-(3-bromo-5H-pyrido[3,2-b]indol-7-yl)acetate, methyl2-(3-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate (4.00 g, 11.4 mmol) andDPPE (5.67 g, 14.2 mmol) were converted to the title compound (1.05 g,29%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.57 (s, 1H), 8.51 (d, J=2.0 Hz, 1H),8.14 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.56-7.52 (m, 1H), 7.45 (dd,J=8.3, 1.7 Hz, 1H), 3.86 (s, 2H), 3.64 (s, 3H); LCMS (M+H)=319.1; HPLCRT=0.78 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with 0.05%TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98% B over1.6 min; Flow: 0.8 mL/min).

Step 4: Methyl2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-8-yl)acetate

A solution of methyl 2-(3-bromo-5H-pyrido[3,2-b]indol-8-yl)acetate (100mg, 0.313 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (242mg, 0.627 mmol), triethylamine (87.0 μl, 0.627 mmol), and copper(I)iodide (8.95 mg, 0.0470 mmol) in DMF (2089 μl) was degassed withbubbling nitrogen.

Tetrakis(triphenylphosphine)palladium(0) (36.2 mg, 0.0310 mmol) wasadded, and the reaction was heated to 90° C. for 4 h. The reaction wascooled, diluted with water, then extracted twice with EtOAc (2×). Theorganic layer was washed with ammonium hydroxide, brine, separated, anddried over sodium sulfate. The solvent was concentrated, and the residuewas purified by column chromatography on silica gel (24 g column,gradient from 0% to 5% MeOH/DCM) to afford the title compound (32.0 mg,31%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.47 (d, J=1.8 Hz, 1H),8.27 (s, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.54-7.49 (m, 1H), 7.48-7.43 (m,1H), 4.03 (s, 3H), 3.86 (s, 2H), 3.75 (s, 3H), 2.39 (s, 3H); LCMS(M+H)=336.2; HPLC RT=0.59 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Step 5:1-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-8-yl]-2-methylpropan-2-ol

Following procedures analogous to those described in Steps 4 and 5 of2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-8-yl)acetate(57.0 mg, 0.170 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(66.0 mg, 0.340 mmol) were converted to the title compound (16.0 mg,19%). ¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J=1.7 Hz, 1H), 8.27 (s, 1H),8.24 (d, J=1.3 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.64 (d, J=7.5 Hz, 2H),7.61 (d, J=1.5 Hz, 1H), 7.39-7.33 (m, 2H), 7.30-7.25 (m, 1H), 5.75 (d,J=11.0 Hz, 1H), 4.01 (s, 3H), 3.99 (br. s., 1H), 3.84 (dd, J=11.1, 2.6Hz, 1H), 3.64-3.56 (m, 1H), 3.46-3.36 (m, 3H), 2.99 (s, 2H), 2.34 (s,3H), 1.63 (dd, J=12.6, 3.9 Hz, 1H), 1.49-1.36 (m, 1H), 1.27 (s, 6H);LCMS (M+H)=510.4; HPLC RT=0.80 min (Column: BEH C18 2.1×50 mm; MobilePhase A: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05%TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Example 2561-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-2-methylpropan-2-ol

Step 1: Ethyl2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)acetate

Following a procedure analogous to that described for methyl2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-8-yl)acetate,ethyl 2-(3-bromo-5H-pyrido[3,2-b]indol-7-yl)acetate (200 mg, 0.600 mmol)and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (464 mg, 1.20mmol) were converted to the title compound (111 mg, 53%). LCMS(M+H)=350.2; HPLC RT=0.66 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Step 2:1-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-2-methylpropan-2-ol

Following procedures analogous to those described in Steps 4 and 5 of2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,ethyl2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)acetate(55.0 mg, 0.160 mmol) and(R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (66.2 mg, 0.320mmol) were converted to the title compound (3.20 mg, 4%). ¹H NMR (500MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.92 (br. s., 1H),7.73 (dd, J=8.2, 5.6 Hz, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.14 (t, J=8.8 Hz,2H), 5.77 (d, J=11.1 Hz, 1H), 4.03 (br. s., 2H), 3.90 (d, J=7.4 Hz, 1H),3.73 (d, J=9.1 Hz, 1H), 3.53-3.35 (m, 1H), 3.26 (t, J=11.1 Hz, 1H), 2.92(br. s., 1H), 2.31 (br. s., 3H), 1.77 (s, 1H), 1.65 (d, J=12.5 Hz, 1H),1.56-1.46 (m, 1H), 1.35-1.22 (m, 1H), 1.20 (d, J=6.1 Hz, 1H), 1.16-1.07(m, 6H), 1.05 (d, J=12.5 Hz, 1H), 0.99 (d, J=6.1 Hz, 1H); LCMS(M+H)=528.3; HPLC RT=0.79 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Example 2575-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Step 1:4,4,5,5-Tetramethyl-2-(2-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane

A suspension of 1-bromo-2-(methylsulfonyl)benzene (800 mg, 3.40 mmol),bis(pinacolato)diboron (1040 mg, 4.08 mmol) and potassium acetate (668mg, 6.81 mmol) in dioxane (4 ml) was degassed with bubbling nitrogen.PdCl₂(dppf)-CH₂Cl₂ adduct (139 mg, 0.170 mmol) was added, and thereaction was heated to 95° C. for 2 h. The reaction was diluted withEtOAc (30 mL) and filtered through Celite. The organic layer was washedwith brine and dried with sodium sulfate. The solvent was evaporated,and the residue was purified by column chromatography on silica gel (40g column, gradient from 0% to 40% EtOAc/hexanes) to give the titlecompound (626 mg, 65%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ8.03 (dd, J=7.6, 1.2 Hz, 1H), 7.72-7.67 (m, 1H), 7.61 (dtd, J=18.6, 7.4,1.5 Hz, 2H), 5.32 (s, 1H), 3.24 (s, 3H), 1.43 (s, 12H); LCMS(M+H)=283.2; HPLC RT=0.89 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Step 2: 5-Bromo-2-(2-(methylsulfonyl)phenyl)-3-nitropyridine

Following a procedure analogous to that described for ethyl2-(4-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate,4,4,5,5-tetramethyl-2-(3-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane(620 mg, 2.20 mmol) and 2,5-dibromo-3-nitropyridine (650 mg, 2.31 mmol)were converted to the title compound (554 mg, 71%). LCMS (M+H)=359.0;HPLC RT=0.81 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98%B over 1.6 min; Flow: 0.8 mL/min).

Step 3: 3-Bromo-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole

Following a procedure analogous to that described for ethyl2-(3-bromo-5H-pyrido[3,2-b]indol-7-yl)acetate,5-bromo-2-(2-(methylsulfonyl)phenyl)-3-nitropyridine (550 mg, 1.54 mmol)and DPPE (767 mg, 1.93 mmol) were converted to the title compound (201mg, 40%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.71 (d, J=2.1 Hz,1H), 8.36 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 0.8 Hz, 1H), 7.90 (dd,J=7.5, 0.9 Hz, 1H), 7.82-7.72 (m, 1H), 3.75 (s, 3H); LCMS (M+H)=327.0;HPLC RT=0.76 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98%B over 1.6 min; Flow: 0.8 mL/min).

Step 4:3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole

Following a procedure analogous to that described for2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-8-yl)acetate,3-bromo-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole (200 mg, 0.615 mmol)and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (475 mg, 1.23mmol) were converted to the title compound (195 mg, 93%). ¹H NMR (400MHz, DMSO-d₆) δ 12.37 (s, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.22 (d, J=2.0Hz, 1H), 8.06-8.00 (m, 1H), 7.93 (dd, J=7.5, 0.7 Hz, 1H), 7.82-7.75 (m,1H), 4.04 (s, 3H), 3.83 (s, 3H), 2.33 (s, 3H); LCMS (M+H)=342.1; HPLCRT=0.60 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with 0.05%TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98% B over1.6 min; Flow: 0.8 mL/min).

Step 5:5-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

To a suspension of3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole(50.0 mg, 0.146 mmol),(R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (61.6 mg, 0.293mmol), and triphenylphosphine (77.0 mg, 0.293 mmol) in THF (1.5 mL)cooled in an ice bath was added DIAD (57.0 μl, 0.293 mmol). Theresulting suspension was stirred at room temperature overnight and thenconcentrated. The residue was purified by reverse phase HPLC (Column:Waters XBridge Phenyl, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-55% B over25 min, then a 5-min hold at 55% B; Flow: 20 mL/min) to give the titlecompound (18.6 mg, 24%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (br. s., 1H),7.96 (s, 2H), 7.88 (br. s., 1H), 7.75 (dd, J=8.1, 5.4 Hz, 2H), 7.18 (t,J=8.6 Hz, 2H), 6.04 (d, J=11.1 Hz, 1H), 4.05 (br. s., 3H), 3.91 (d,J=5.7 Hz, 1H), 3.81 (s, 3H), 3.72 (d, J=9.8 Hz, 1H), 3.49 (d, J=10.8 Hz,1H), 3.25 (t, J=11.6 Hz, 1H), 2.33 (br. s., 3H), 1.72 (d, J=11.8 Hz,1H), 1.58 (d, J=9.4 Hz, 1H), 1.29 (d, J=9.4 Hz, 1H), 0.94 (br. s., 1H);LCMS (M+H)=534.2; HPLC RT=0.83 min (Column: Chromolith ODS S5 4.6×50 mm;Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 4 mL/min).

Example 2582-{1-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-methanesulfonyl-5H-pyrido[3,2-b]indol-5-yl]-4,4,4-trifluorobutyl}pyridine

Following a procedure analogous to that described for5-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole(50.0 mg, 0.150 mmol) and 4,4,4-trifluoro-1-(pyridin-2-yl)butan-1-ol(60.1 mg, 0.290 mmol) were converted to racemic2-{1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-methanesulfonyl-5H-pyrido[3,2-b]indol-5-yl]-4,4,4-trifluorobutyl}pyridine,which was separated using chiral prep SFC (Column: Chiral OD-H 25×3 cm,5 μm; Mobile Phase: 77/23 CO₂/MeOH; Flow: 85 mL/min). The slower elutingpeak was concentrated to give 11.2 mg (15%). ¹H NMR (400 MHz, CD₃OD) δ8.72 (d, J=1.8 Hz, 1H), 8.64 (d, J=5.6 Hz, 1H), 8.22-8.15 (m, 2H), 8.10(d, J=7.2 Hz, 1H), 7.85-7.78 (m, 1H), 7.74 (td, J=0.7, 1.8 Hz, 1H), 7.35(dd, J=7.1, 5.0 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 6.44 (dd, J=10.3, 6.0Hz, 1H), 4.01 (s, 3H), 3.80 (s, 3H), 3.16-3.06 (m, 1H), 2.99-2.86 (m,1H), 2.49-2.36 (m, 1H), 2.30 (s, 3H), 1.97-1.83 (m, 1H); LCMS(M+H)=529.3; HPLC RT=0.85 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Example 2595-{9-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following a procedure analogous to that described for5-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-(methylsulfonyl)-5H-pyrido[3,2-b]indole(50.0 mg, 0.150 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(56.3 mg, 0.290 mmol) were converted to the title compound (15.0 mg,20%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (d, J=1.3 Hz, 1H), 8.84 (d, J=8.4Hz, 1H), 8.77 (br. s., 1H), 8.69 (s, 1H), 8.16 (d, J=7.7 Hz, 1H),7.98-7.93 (m, 2H), 7.86 (br. s., 1H), 7.28-7.22 (m, 1H), 6.03 (d, J=11.1Hz, 1H), 5.36 (quin, J=6.2 Hz, 1H), 4.09 (s, 3H), 3.91 (br. s., 1H),3.81 (s, 3H), 3.72 (d, J=9.1 Hz, 1H), 3.50 (d, J=11.8 Hz, 1H), 3.26 (t,J=11.6 Hz, 1H), 2.36 (s, 3H), 1.76 (d, J=12.8 Hz, 1H), 1.63-1.56 (m,1H), 1.31 (d, J=9.8 Hz, 1H), 0.93 (d, J=10.8 Hz, 1H); LCMS (M+H)=516.3;HPLC RT=0.83 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98%B over 1.6 min; Flow: 0.8 mL/min).

Example 2602-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Following a procedure analogous to that described for4,4,5,5-tetramethyl-2-(2-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane,methyl 4-bromo-3-methoxybenzoate (1.30 g, 5.30 mmol) andbis(pinacolato)diboron (1.62 g, 6.37 mmol) were converted to the titlecompound (820 mg, 53%). LCMS (M+H)=293.2; HPLC RT=0.97 min (Column: BEHC18 2.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min).

Step 2: Methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-methoxybenzoate

Following a procedure analogous to that described for ethyl2-(4-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate, methyl3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (820mg, 2.81 mmol) and 2,5-dibromo-3-nitropyridine (831 mg, 2.95 mmol) wereconverted to the title compound (705 mg, 68%). LCMS (M+H)=367.0; HPLCRT=0.98 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with 0.05%TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98% B over1.6 min; Flow: 0.8 mL/min).

Step 3: Methyl 3-bromo-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described for ethyl2-(3-bromo-5H-pyrido[3,2-b]indol-7-yl)acetate, methyl4-(5-bromo-3-nitropyridin-2-yl)-3-methoxybenzoate (620 mg, 1.69 mmol)and DPPE (841 mg, 2.11 mmol) were converted to the title compound (238mg, 42%). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J=2.0 Hz, 1H), 8.10 (d,J=2.0 Hz, 1H), 7.85 (d, J=1.1 Hz, 1H), 7.42 (d, J=1.0 Hz, 1H), 4.14 (s,3H), 3.99 (s, 3H); LCMS (M+H)=335.1; HPLC RT=0.74 min (Column: BEH C182.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min).

Step 4: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described for2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-8-yl)acetate,methyl 3-bromo-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (235 mg,0.700 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (542mg, 1.40 mmol) were converted to the title compound (151 mg, 61%). ¹HNMR (400 MHz, CDCl₃) δ 11.76 (br. s., 1H), 8.56 (s, 1H), 7.90 (s, 1H),7.80 (d, J=6.8 Hz, 1H), 7.42 (s, 1H), 4.19 (s, 3H), 3.95 (s, 3H), 3.91(s, 3H), 2.30 (s, 3H); LCMS (M+H)=352.2; HPLC RT=0.61 min (Column: BEHC18 2.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B:Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8mL/min).

Step 5:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following procedures analogous to those described in Steps 4 and 5 of2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(150 mg, 0.430 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(123 mg, 0.640 mmol) were converted to the title compound (7.90 mg, 4%).¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J=1.7 Hz, 1H), 7.53-7.50 (m, 2H),7.44 (d, J=7.2 Hz, 2H), 7.37-7.31 (m, 2H), 6.95 (s, 1H), 6.37 (br. s.,2H), 5.58 (d, J=10.5 Hz, 1H), 4.21 (s, 3H), 4.07 (dd, J=12.0, 2.7 Hz,1H), 3.86 (s, 3H), 3.61-3.51 (m, 1H), 3.40-3.30 (m, 1H), 3.08 (d, J=10.9Hz, 1H), 2.28 (s, 3H), 2.09-2.00 (m, 2H), 1.76 (d, J=3.4 Hz, 6H), 1.66(td, J=12.4, 4.0 Hz, 2H), 1.41 (dd, J=12.8, 4.2 Hz, 1H); LCMS(M+H)=526.5; HPLC RT=0.71 min (Column: BEH C18 2.1×50 mm; Mobile PhaseA: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA;Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).

Example 2611-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-2-methylpropan-2-ol

Following procedures analogous to those described in Steps 4 and 5 of2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,ethyl2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)acetate(55.0 mg, 0.160 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(60.5 mg, 0.320 mmol) were converted to the title compound (3.20 mg,4%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (s, 2H), 8.15 (d, J=8.1 Hz, 1H),7.95 (s, 1H), 7.69 (d, J=7.7 Hz, 2H), 7.35-7.28 (m, 2H), 7.24 (t, J=7.7Hz, 2H), 5.79 (d, J=11.1 Hz, 1H), 4.02 (br. s., 3H), 3.89 (d, J=7.1 Hz,1H), 3.73 (d, J=10.1 Hz, 1H), 3.52-3.38 (m, 2H), 3.27 (t, J=11.4 Hz,1H), 2.94 (s, 2H), 2.31 (s, 3H), 1.68 (d, J=12.8 Hz, 1H), 1.53 (d, J=9.1Hz, 1H), 1.35-1.25 (m, 1H), 1.12 (d, J=10.4 Hz, 6H); LCMS (M+H)=510.3;HPLC RT=0.78 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98%B over 1.6 min; Flow: 0.8 mL/min).

Example 2622-{3-[4-(²H₃)Methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: 4-(²H₃)Methyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole

A solution of sodium ascorbate (344 mg, 1.74 mmol) in water (2170 μL)was added to a stirred solution of trimethyl(²H₃-prop-1-yn-1-yl)silane(prepared according to PCT Int. Appl., 2007112352, 4 Oct. 2007, 200 mg,1.74 mmol) and (azidomethyl)trimethylsilane (294 mg, 1.91 mmol) int-BuOH (4340 μL) at ambient temperature. Copper (II) sulfatepentahydrate (87.0 mg, 0.347 mmol) in water (2170 μL) was subsequentlyadded in a drop wise fashion. The reaction was stirred at ambienttemperature for 16 h before it was diluted with water (10 mL) and ethylacetate (20 mL). The 2 layers were separated, and the aqueous layer waswashed with additional ethyl acetate (2×20 mL). The combined organicswere dried over sodium sulfate, the solids were filtered away, and thevolatiles were removed under reduced pressure. The crude material waspurified using silica gel column chromatography with a gradient of ethylacetate in hexanes (0-60%).4-(²H₃)Methyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (125 mg,0.725 mmol, 42%) was isolated as a colorless oil. ¹H NMR (500 MHz,CDCl₃) δ 7.16 (br. s., 1H), 3.89 (s, 2H), 0.15 (s, 9H); LC/MS(M+H)=173.2; LC/MS RT=1.20 min (Column: Phenomenex Luna 30×2.0 mm 3 u;Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B:90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 2 min; Flow: 1 mL/min).

Step 2: Methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

(S)-Methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(174 mg, 0.363 mmol),4-(²H₃)methyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (125 mg,0.725 mmol), bis(triphenylphosphine) palladium(II) chloride (25.5 mg,0.0360 mmol), and tetramethylammonium acetate (72.5 mg, 0.544 mmol) werestirred in NMP (1810 μL) at 90° C. under N₂ (g) for 16 h. The reactionmixture was subsequently allowed to cool to ambient temperature beforeadditional portions of bis(triphenylphosphine) palladium (II) chloride(25.5 mg, 0.0360 mmol) and tetramethylammonium acetate (72.5 mg, 0.544mmol) were added. The reaction vessel was purged with N₂ (g) and heatedfor an additional 24 h. The volatiles were removed under reducedpressure, and the crude material was purified using silica gel columnchromatography with a gradient of ethyl acetate in hexanes (0-100%) toafford methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(51.0 mg, 0.102 mmol, 28%). ¹H NMR (DMSO-d₆) δ: 8.73 (br. s., 1H), 8.64(s, 1H), 8.53 (br. s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz,1H), 7.67 (d, J=7.3 Hz, 2H), 7.32-7.37 (m, 2H), 7.24-7.28 (m, 1H), 6.00(d, J=11.4 Hz, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 3.86-3.93 (m, 1H), 3.72(d, J=8.8 Hz, 1H), 3.35-3.52 (m, 2H), 3.25 (t, J=11.6 Hz, 1H), 1.59-1.77(m, 2H), 1.27-1.40 (m, 1H), 0.96 (d, J=13.9 Hz, 1H); LC/MS (M+H)=499.3;LC/MS RT=1.10 min (Column: Waters Aquity BEH C18 2.1×50 mm 1.7 u; MobilePhase A: water with 0.05% TFA; Mobile Phase B: acetonitrile with 0.05%TFA; Temperature: 40° C.; Gradient: 2-98% B over 1.5 min; Flow: 0.8mL/min).

Step 3:2-{3-[4-(²H₃)Methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Methyllithium (251 μl, 0.401 mmol) in Et₂O was added to a stirredsolution of methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(50.0 mg, 0.100 mmol) in THF (1000 μL) under N₂ (g) at −78° C. Thereaction was stirred at that temperature for 1 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride (8 mL) and dilutedwith ethyl acetate (20 mL) while still at −78° C. The mixture wasremoved from the cold bath and allowed to warm to ambient temperature.The layers were separated, and the aqueous phase was washed with asecond portion of ethyl acetate (20 mL). The combined organics weredried over sodium sulfate, the solids were filtered away, and thevolatiles were removed under reduced pressure. The crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: waterwith 10-mM ammonium acetate; Gradient: 40-100% B over 5 min, then a20-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% Bover 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(6.70 mg, 0.0130 mmol, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (s, 1H),8.41 (br. s., 1H), 8.15 (d, J=8.1 Hz, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.48(d, J=8.4 Hz, 1H), 7.36-7.29 (m, 2H), 7.28-7.21 (m, 1H), 5.82 (d, J=11.0Hz, 1H), 5.26 (s, 1H), 4.01 (s, 3H), 3.90 (d, J=10.3 Hz, 1H), 3.75 (d,J=9.2 Hz, 1H), 3.53-3.36 (m, 2H), 3.27 (t, J=11.0 Hz, 1H), 1.72 (d,J=12.5 Hz, 1H), 1.59 (s, 7H), 1.40-1.25 (m, 1H), 1.02 (d, J=12.1 Hz,1H);); LC/MS (M+H)=499.3; LC/MS RT=0.92 min (Column: Waters Aquity BEHC18 2.1×50 mm 1.7 u; Mobile Phase A: water with 0.05% TFA; Mobile PhaseB: acetonitrile with 0.05% TFA; Temperature: 40° C.; Gradient: 2-98% Bover 1.5 min; Flow: 0.8 mL/min).

Example 2635-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Step 1: 4-(²H₃)Methyl-1-methyl-1H-1,2,3-triazole

TBAF (60.9 ml, 60.9 mmol) was added drop wise to a stirred solution of4-(²H₃)methyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (prepared inroute to methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate,8.75 g, 50.8 mmol) and water (1.83 mL, 102 mmol) in THF (203 mL) at 0°C. The reaction was stirred at that temperature for 1 h before it wasremoved from the cold bath and allowed to warm to ambient temperature.The reaction mixture was stirred at ambient temperature for 16 h. Thevolatiles were removed from the aqueous layer under reduced pressure.The resulting oil was purified using silica gel column chromatographywith a gradient of methanol in ethyl acetate (0-20%).1-Methyl-4-(²H₃)methyl-1H-1,2,3-triazole (4.67 g, 46.6 mmol, 92%) wasisolated as a yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 7.76 (s, 1H), 3.98(s, 3H); LC/MS (M+H)=101.2; LC/MS RT=0.57 min (Column: Waters Aquity BEHC18 2.1×50 mm 1.7 u; Mobile Phase A: water with 0.05% TFA; Mobile PhaseB: acetonitrile with 0.05% TFA; Temperature: 40° C.; Gradient: 2-98% Bover 1.5 min; Flow: 0.8 mL/min).

Step 2: 4-(²H₃)Methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole

n-BuLi (9.59 mL, 24.0 mmol) in hexanes was added drop wise to a stirredsolution of 1-methyl-4-(²H₃)methyl-1H-1,2,3-triazole (2.00 g, 20.0 mmol)in THF (49.9 mL) at −78° C. under N₂ (g). A white precipitate formedupon addition. The reaction was stirred at that temperature for 30 minbefore tributyltin chloride (5.96 mL, 22.0 mmol) was added drop wise.The reaction was stirred for an additional 10 min before the cold bathwas removed, and the reaction was allowed to warm to ambient temperatureover 30 min. The reaction mixture was quenched with saturated aqueousammonium chloride (20 mL) and diluted with 10% aqueous LiCl (20 mL). Thelayers were separated and the aqueous layer was washed with diethylether (3×30 mL). The combined organics were dried over sodium sulfate,the solids were filtered away, and the volatiles were removed underreduced pressure. The crude material was purified using silica gelcolumn chromatography with a gradient of ethyl acetate in hexanes(0-50%). 1-Methyl-5-(tributylstannyl)-4-(²H₃)methyl-1H-1,2,3-triazole(6.02 g, 15.5 mmol, 77%) was isolated as a colorless oil. ¹H NMR (500MHz, DMSO-d₆) δ 3.97 (s, 3H), 1.62-1.39 (m, 6H), 1.35-1.25 (m, 6H),1.24-1.10 (m, 6H), 0.91-0.83 (m, 9H).

Step 3:5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

A solution of(S)-3-bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(139 mg, 0.278 mmol),1-methyl-5-(tributylstannyl)-4-(²H₃)methyl-1H-1,2,3-triazole (119 mg,0.306 mmol), tetrakis(triphenylphosphine)palladium(0) (32.2 mg, 0.0280mmol), copper (I) iodide (10.6 mg, 0.0560 mmol), and triethylamine (46.6μL, 0.334 mmol) in DMF (2783 μL) was degassed using N₂ (g) for 3 min.The reaction mixture was then heated to 80° C. for 16 h. The volatileswere removed under reduced pressure, and the crude material was purifiedusing silica gel column chromatography with a gradient of methanol inethyl acetate (0-20%).5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(114.0 mg, 0.215 mmol, 77%) was isolated as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.78 (br. s., 1H), 8.68 (d, J=1.3 Hz, 1H), 8.56 (br. s.,1H), 8.49 (d, J=8.2 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.70 (d, J=7.7 Hz,2H), 7.38-7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.03 (d, J=11.3 Hz, 1H), 4.02(s, 3H), 3.91 (d, J=7.9 Hz, 1H), 3.74 (d, J=8.5 Hz, 1H), 3.54-3.44 (m,2H), 3.41 (s, 3H), 3.31-3.23 (m, 1H), 1.73 (d, J=13.1 Hz, 1H), 1.68-1.56(m, 1H), 1.44-1.30 (m, 1H), 0.97 (d, J=11.7 Hz, 1H); LC/MS (M+H)=519.3;LC/MS RT=1.41 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile PhaseA: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Examples 264-267

The compounds in Table 9 were prepared according to the proceduresdescribed for5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.Conversion of methyl ester intermediates into final compounds wascarried out according to the procedure described for2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(Step 3):

TABLE 9 LC/MS LC/ LC/ RT MS MS (M + Meth- Example R¹ Y (min) H) od 264CH₃O₂S—

1.46 537.2 A 265 CH₃O₂S—

1.88 537.2 B 266 HO(CH₃)₂C—

1.39 517.3 A 267 HO(CH₃)₂C—

1.49 517.3 A

-   -   HPLC Conditions for Table 9: Method A: Column: Phenomenex Luna        30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with        0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1%        TFA; Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1        mL/min. Method B: Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile        Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10        MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%        B over 2 min; Flow: 1 mL/min.

Example 2685-{9-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Step 1:5-{9-Methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

A solution of 3-bromo-9-methanesulfonyl-5H-pyrido[3,2-b]indole (preparedin route to5-{5-[(2-fluorophenyl)(oxan-4-yl)methyl]-9-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,300 mg, 0.923 mmol),4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (395 mg,1.02 mmol), tetrakis(triphenylphosphine)palladium(0) (107 mg, 0.0920mmol), copper (I) iodide (35.1 mg, 0.185 mmol), and Et₃N (154 μL, 1.11mmol) in DMF (9230 μL) was degassed using N₂ (g) for 3 min. The reactionmixture was then heated to 80° C. for 16 h. The crude reaction mixturewas purified using silica gel column chromatography with a gradient ofmethanol in ethyl acetate (0-5%).5-{9-Methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(121 mg, 0.352 mmol, 38%) was isolated as a gummy solid. ¹H NMR (500MHz, DMSO-d₆) δ 12.37 (s, 1H), 8.75 (d, J=1.9 Hz, 1H), 8.23 (d, J=1.9Hz, 1H), 8.03 (dd, J=8.2, 0.9 Hz, 1H), 7.93 (dd, J=7.5, 0.9 Hz, 1H),7.79 (t, J=7.9 Hz, 1H), 4.05 (s, 3H), 3.83 (s, 3H); LC/MS (M+H)=345.2;LC/MS RT=1.04 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile PhaseA: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Step 2: (R)-Cyclohexyl(phenyl)methyl methanesulfonate

Methanesulfonyl chloride (24.3 μL, 0.312 mmol) was added drop wise to astirred solution of (R)-cyclohexyl(phenyl)methanol (prepared in route to(S)-2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,40.0 mg, 0.208 mmol) and Et₃N (58.0 μL, 0.416 mmol) in DCM (2080 μL) at0° C. under N₂ (g). The reaction was stirred for 15 min before thereaction vessel was removed from the cold bath, and the reaction mixturewas allowed to warm to ambient temperature over 1 h. The reactionmixture was quenched with saturated aqueous NaHCO₃ (5 mL). The layerswere separated, and the aqueous layer was washed with diethyl ether (2×7mL). The combined organics were dried over sodium sulfate, the solidswere filtered away, and the volatiles were removed under reducedpressure. The product was used without additional purification.

Step 3:5-{9-Methanesulfonyl-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

5-{9-Methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(40.0 mg, 0.116 mmol), (R)-cyclohexyl(phenyl)methyl methanesulfonate(62.8 mg, 0.232 mmol), and cesium carbonate (151 mg, 0.465 mmol) werestirred in DMF (581 μL) at 60° C. under N₂ (g) for 16 h. The volatileswere removed under reduced pressure, and the crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-65% B over 15 min, then a5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to afford5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(12.7 mg, 0.0240 mmol, 21%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.86-8.34 (m,3H), 7.96 (d, J=7.0 Hz, 1H), 7.92-7.77 (m, 1H), 7.69 (d, J=7.7 Hz, 2H),7.37-7.31 (m, 2H), 7.30-7.23 (m, 1H), 6.02 (d, J=11.0 Hz, 1H), 4.04 (br.s., 3H), 3.91 (d, J=10.6 Hz, 1H), 3.80 (s, 3H), 3.72 (d, J=8.8 Hz, 1H),3.53-3.45 (m, 1H), 3.40 (br. s., 1H), 3.27 (t, J=11.4 Hz, 1H), 1.75 (d,J=11.4 Hz, 1H), 1.65-1.53 (m, 1H), 1.37-1.23 (m, 1H), 0.94 (d, J=11.7Hz, 1H); LC/MS (M+H)=519.3; LC/MS RT=1.46 min (Column: Phenomenex Luna30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA;Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Examples 269 & 270

The compounds in Table 10 were prepared according to the proceduresdescribed for5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole:

TABLE 10 LC/MS RT LC/MS LC/MS Example Y (min) (M + H) Method 269

1.06 537.1 A 270

1.49 537.3 B

-   -   HPLC Conditions for Table 10: Method A: Column: Waters Aquity        BEH C18 2.1×50 mm 1.7 u; Mobile Phase A: water with 0.05% TFA;        Mobile Phase B: acetonitrile with 0.05% TFA; Temperature: 40°        C.; Gradient: 2-98% B over 1.5 min; Flow: 0.8 mL/min. Method B:        Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90        acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10        acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient:        0-100% B over 2 min; Flow: 1 mL/min.

Example 2712-{6-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(prepared in route to(1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol,12.5 mg, 0.0370 mmol),(R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate(prepared according to Step 2 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,15.8 mg, 0.0550 mmol), and cesium carbonate (29.7 mg, 0.0910 mmol) werestirred in DMF (183 μL) at 60° C. under N₂ (g) for 16 h. A secondportion of (R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methylmethanesulfonate (15.8 mg, 0.0550 mmol) and cesium carbonate (29.7 mg,0.0910 mmol) were added. The reaction was heated to 60° C. for anadditional 16 h. The volatiles were removed under reduced pressure, andthe material was used without additional purification. LC/MS(M+H)=535.4; LC/MS RT=1.66 min (Column: Phenomenex Luna 30×2.0 mm 3 u;Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B:90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 2 min; Flow: 1 mL/min).

Step 2:2-{6-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Methylmagnesium bromide (355 μL, 1.07 mmol, 3 M) was added to a stirredsolution of methyl6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(19.0 mg, 0.0360 mmol) in THF (355 μL) under N₂ (g) at −20° C. Thereaction mixture was stirred at that temperature for 1 h. The reactionmixture was then quenched with saturated aqueous ammonium chloride (8mL) and diluted with ethyl acetate (20 mL) while still at −20° C. Themixture was removed from the cold bath and allowed to warm to ambienttemperature. The layers were separated, and the aqueous phase was washedwith a second portion of ethyl acetate (20 mL). The combined organicswere dried over sodium sulfate, the solids were filtered away, and thevolatiles were removed under reduced pressure. The crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford2-{6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(1.30 mg, 2.47 μmol, 7%). LC/MS (M+H)=535.4; LC/MS RT=1.49 min (Column:Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:waterwith 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Example 2722-{6-Fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{6-Fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(3.60 mg, 6.73 μmol, 19%) was prepared according to the proceduresdescribed for2-{6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.LC/MS (M+H)=535.4; LC/MS RT=1.44 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Example 2732-{9-Methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate

A solution of methyl3-bromo-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (prepared inroute to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(2-fluorophenyl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,300 mg, 0.895 mmol),1-methyl-5-(tributylstannyl)-4-(²H₃)methyl-1H-1,2,3-triazole (preparedin route to5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,383 mg, 0.985 mmol), tetrakis(triphenylphosphine)palladium(0) (103 mg,0.0900 mmol), copper (I) iodide (34.1 mg, 0.179 mmol), and Et₃N (150 μL,1.07 mmol) in DMF (8950 μL) was degassed using N₂ (g) for 3 min. Thereaction mixture was then heated to 80° C. for 16 h. The crude reactionmixture was purified using silica gel column chromatography with agradient of methanol in ethyl acetate (0-10%). Methyl9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylatewas isolated as a yellow crystalline solid (239 mg, 0.673 mmol, 75%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.59 (s, 1H), 8.09 (d, J=1.5 Hz,1H), 7.85 (s, 1H), 7.32 (s, 1H), 4.08 (s, 3H), 4.01 (s, 3H), 3.93 (s,3H); LC/MS (M+H)=555.3; LC/MS RT=1.03 min (Column: Phenomenex Luna30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA;Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 2: Methyl9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(40.0 mg, 0.113 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methylmethanesulfonate (prepared in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,61.0 mg, 0.226 mmol), and cesium carbonate (147 mg, 0.451 mmol) werestirred in DMF (564 μL) at 60° C. under N₂ (g) for 16 h. The volatileswere removed under reduced pressure, and the material was used withoutadditional purification. LC/MS (M+H)=529.5; LC/MS RT=1.39 min (Column:Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:waterwith 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 3:2-{9-Methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Methylmagnesium bromide (1120 μL, 3.35 mmol) was added to a stirredsolution of methyl9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(59.0 mg, 0.112 mmol) in THF (1120 μL) under N₂ (g) at −20° C. Thereaction was stirred at that temperature for 1 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride (8 mL) and dilutedwith ethyl acetate (20 mL) while still at −20° C. The reaction mixturewas removed from the cold bath and allowed to warm to ambienttemperature. The layers were separated, and the aqueous phase was washedwith a second portion of ethyl acetate (20 mL). The combined organicswere dried over sodium sulfate, the solids were filtered away, and thevolatiles were removed under reduced pressure. The crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: waterwith 10-mM ammonium acetate; Gradient: 30-70% B over 30 min, then a5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to afford2-{9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(20.4 mg, 0.0370 mmol, 33%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (s, 1H),8.38-8.22 (m, 1H), 7.74-7.59 (m, 3H), 7.36-7.28 (m, 2H), 7.28-7.21 (m,1H), 7.01 (s, 1H), 5.78 (d, J=11.4 Hz, 1H), 4.03-3.95 (m, 6H), 3.89 (d,J=12.1 Hz, 1H), 3.74 (d, J=10.6 Hz, 1H), 3.51-3.45 (m, 2H), 3.25 (t,J=11.4 Hz, 1H), 1.73 (d, J=13.6 Hz, 1H), 1.59 (d, J=6.6 Hz, 7H),1.35-1.20 (m, 1H), 0.97 (d, J=13.2 Hz, 1H); LC/MS (M+H)=529.5; LC/MSRT=1.18 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A:10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Examples 274 & 275

The compounds in Table 11 were prepared according to the proceduresdescribed for2-{9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol:

TABLE 11 LC/MS RT LC/MS LC/MS Example Y (min) (M + H) Method 274

1.19 547.8 A 275

1.21 547.5 A

-   -   HPLC Conditions for Table 11: Method A: Column: Phenomenex Luna        30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with        0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1%        TFA; Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1        mL/min.

Example 2762-{8-Fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl8-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(prepared in route to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,105 mg, 0.307 mmol),(R)-(2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate(prepared similarly to Step 2 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole,221 mg, 0.767 mmol), and cesium carbonate (400 mg, 1.23 mmol) werestirred in DMF (1530 μL) at 60° C. under N₂ (g) for 16 h. The volatileswere removed under reduced pressure, and methyl8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylatewas used without additional purification. LC/MS (M+H)=535.3; LC/MSRT=2.48 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A:10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Step 2:2-{8-Fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Methylmagnesium bromide (2990 μL, 8.98 mmol) was added to a stirredsolution of methyl8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(160 mg, 0.299 mmol) in THF (2990 μL) under N₂ (g) at −20° C. Thereaction was stirred at that temperature for 1 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride (8 mL) and dilutedwith ethyl acetate (20 mL) while still at −20° C. The mixture wasremoved from the cold bath and allowed to warm to ambient temperature.The layers were separated, and the aqueous phase was washed with asecond portion of ethyl acetate (20 mL). The combined organics weredried over sodium sulfate, the solids were filtered away, and thevolatiles were removed under reduced pressure. The crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation.

The material was further purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; MobilePhase B: 95:5 methanol: water with 10-mM ammonium acetate; Gradient:40-80% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford2-{8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(16.3 mg, 0.0290 mmol, 10%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (s, 1H),8.42 (br. s., 1H), 8.14 (br. s., 2H), 7.88 (d, J=11.0 Hz, 1H), 7.43-7.28(m, 2H), 7.17-7.10 (m, 1H), 5.94 (br. s., 1H), 5.55 (s, 1H), 4.00 (br.s., 3H), 3.90 (d, J=9.2 Hz, 1H), 3.72 (d, J=11.0 Hz, 1H), 3.54-3.44 (m,1H), 3.40 (br. s., 1H), 3.26-3.11 (m, 1H), 1.74 (d, J=11.7 Hz, 1H),1.64-1.48 (m, 7H), 1.32 (d, J=11.7 Hz, 1H), 0.79 (br. s., 1H); LC/MS(M+H)=535.3; LC/MS RT=2.23 min (Column: Phenomenex Luna 30×2.0 mm 3 u;Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B:90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 2 min; Flow: 1 mL/min).

Example 277

2-{8-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1:2-{8-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{8-Fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(12.3 mg, 22.0 μmol, 7%) was prepared according to the proceduresdescribed for2-{8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.44 (br. s., 1H), 8.21 (br.s., 1H), 7.90 (d, J=11.0 Hz, 1H), 7.72-7.66 (m, 2H), 7.18 (t, J=8.8 Hz,2H), 5.76 (d, J=10.6 Hz, 1H), 5.61 (s, 1H), 4.01 (s, 3H), 3.90 (d, J=8.8Hz, 1H), 3.74 (d, J=9.2 Hz, 1H), 3.41-3.38 (m, 2H), 3.25 (t, J=11.2 Hz,1H), 1.68 (d, J=13.2 Hz, 1H), 1.64-1.44 (m, 7H), 1.36-1.21 (m, 1H), 0.97(d, J=12.8 Hz, 1H); LC/MS (M+H)=535.3; LC/MS RT=2.30 min (Column:Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:waterwith 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Example 2782-{6-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1:5-{7-Chloro-6-fluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

5-{7-Chloro-6-fluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(680 mg, 2.13 mmol, 85%) was prepared from3-bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indole (prepared in route to1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol)according to Step 1 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.63 (d, J=2.0 Hz, 1H),8.11-8.05 (m, 2H), 7.43 (dd, J=8.6, 6.4 Hz, 1H), 4.01 (s, 3H); LC/MS(M+H)=319.2; LC/MS RT=1.30 min (Column: Phenomenex Luna 30×2.0 mm 3 u;Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B:90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 2 min; Flow: 1 mL/min).

Step 2:5-{7-Chloro-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Di-tert-butyl azodicarboxylate (108 mg, 0.471 mmol) in THF (1 mL) wasadded drop wise to a stirred solution of triphenylphosphine (123 mg,0.471 mmol) in THF (2350 μL) at 0° C. The reaction mixture was stirredfor 10 min before (R)-oxan-4-yl(phenyl)methanol (prepared in route to(S)-2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,90.0 mg, 0.471 mmol) was added in a single portion. The reaction wasstirred for an additional 10 min before3-bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indole (75.0 mg, 0.235 mmol)in THF (1 mL) was added drop wise over an additional 10 min. Thereaction mixture was allowed to warm to ambient temperature over 16 h.TFA (181 μL, 2.35 mmol) was added, and the reaction mixture was stirredfor 10 min. Monobasic potassium phosphate (5 mL, 1.5 M) was added to thereaction mixture, followed by ethyl acetate (10 mL). The layers wereseparated, and the organics were dried over sodium sulfate. The aqueouslayer was washed with ethyl acetate (2×10 mL), and the combined organicswere dried over sodium sulfate. The solids were filtered away, and thevolatiles were removed under reduced pressure. The crude material waspurified using reverse phase preparatory HPLC (TFA/acetonitrile/water).5-{7-Chloro-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole (116 mg,0.235 mmol, 100%) was isolated as a yellow oil. LC/MS (M+H)=494.1; LC/MSRT=1.88 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A:10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Step 3:1-{6-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-one

A solution of5-{7-chloro-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(116 mg, 0.235 mmol), tributyl(1-ethoxyvinyl)tin (170 mg, 0.471 mmol),Pd₂(dba)₃ (21.6 mg, 0.0240 mmol), tricyclohexylphosphine (13.2 mg,0.0470 mmol), and cesium carbonate (153 mg, 0.471 mmol) in dioxane (2350μL) was degassed with N₂ (g) for 3 min. The reaction mixture wassubsequently stirred at 105° C. for 72 h. 1N Aqueous HCl (2 mL) wasadded drop wise, and the reaction mixture was stirred for 20 min. Thereaction mixture was quenched with 1.5 M aqueous monobasic potassiumphosphate (5 mL), and the layers were separated. The aqueous layer waswashed with ethyl acetate (3×10 mL). The combined organics were driedover sodium sulfate. The solids were filtered away, and the volatileswere removed under reduced pressure.1-{6-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-onewas used without additional purification. LC/MS (M+H)=501.5; LC/MSRT=1.60 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A:10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Step 4:2-{6-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Methylmagnesium bromide (2360 μL, 7.07 mmol) was added to a stirredsolution of1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-one(118 mg, 0.236 mmol) in THF (2360 μL) under N₂ (g) at −20° C. Thereaction was stirred at that temperature for 1 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride (8 mL) and dilutedwith ethyl acetate (20 mL) while still at −20° C. The mixture wasremoved from the cold bath and allowed to warm to ambient temperature.The layers were separated, and the aqueous phase was washed with asecond portion of ethyl acetate (20 mL). The combined organics weredried over sodium sulfate, the solids were filtered away, and thevolatiles were removed under reduced pressure. The crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(11.1 mg, 0.0210 mmol, 9%). ¹H NMR (DMSO-d₆) δ: 8.51 (br. s., 1H), 8.17(br. s., 1H), 8.02 (d, J=8.1 Hz, 1H), 7.54-7.66 (m, 3H), 7.29-7.37 (m,2H), 7.21-7.28 (m, 1H), 5.97 (br. s., 1H), 3.82-3.97 (m, 4H), 3.75 (d,J=7.7 Hz, 1H), 3.48 (t, J=11.0 Hz, 2H), 3.28 (t, J=11.6 Hz, 1H), 1.79(d, J=11.7 Hz, 1H), 1.68 (s, 6H), 1.33 (d, J=10.6 Hz, 2H), 1.07 (d,J=12.1 Hz, 1H); LC/MS (M+H)=517.5; LC/MS RT=1.46 min (Column: PhenomenexLuna 30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1%TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Example 2792-{8-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1:5-{7-Chloro-8-fluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

5-{7-Chloro-8-fluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole (334 mg, 1.05 mmol, 78%) was prepared from3-bromo-7-chloro-8-fluoro-5H-pyrido[3,2-b]indole (prepared in route to1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol)according to Step 1 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.¹H NMR (500 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.20(d, J=9.0 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.85 (d, J=6.0 Hz, 1H), 4.01(s, 1H); LC/MS (M+H)=319.2; LC/MS RT=1.28 min (Column: Phenomenex Luna30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA;Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 2:5-{7-Chloro-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

5-{7-Chloro-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(60.7 mg, 0.123 mmol, 78%) was prepared from5-{7-chloro-8-fluoro-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazoleaccording to Step 2 in route to2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.LC/MS (M+H)=493.5; LC/MS RT=1.74 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 3:1-{8-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-one

1-{8-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-onewas prepared from5-{7-chloro-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazoleaccording to Step 3 in route to2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.LC/MS (M+H)=501.3; LC/MS RT=1.15 min (Column: Waters Aquity BEH C182.1×50 mm 1.7 u; Mobile Phase A: water with 0.05% TFA; Mobile Phase B:acetonitrile with 0.05% TFA; Temperature: 40° C.; Gradient: 2-98% B over1.5 min; Flow: 0.8 mL/min).

Step 4:2-{8-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{8-Fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(4.40 mg, 8.52 μmol, 17%) was prepared from1-{8-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-oneaccording to Step 4 in route to2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.¹H NMR (DMSO-d₆) δ: 8.53 (s, 1H), 8.38-8.49 (m, 1H), 8.20-8.27 (m, 1H),7.89 (d, J=11.0 Hz, 1H), 7.66 (d, J=7.7 Hz, 2H), 7.31-7.39 (m, 2H),7.23-7.30 (m, 1H), 5.74 (d, J=11.4 Hz, 1H), 4.01 (s, 3H), 3.90 (d,J=10.6 Hz, 1H), 3.74 (d, J=9.5 Hz, 1H), 3.46 (t, J=11.6 Hz, 1H),3.32-3.39 (m, 1H), 3.26 (t, J=11.2 Hz, 1H), 1.71 (d, J=12.5 Hz, 1H),1.48-1.65 (m, 7H), 1.31 (d, J=9.2 Hz, 1H), 0.98 (d, J=12.5 Hz, 1H);LC/MS (M+H)=517.3; LC/MS RT=1.45 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Examples 280 & 2812-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(400 mg, 1.23 mmol, 100%) was prepared from methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate according to Step 1 inroute to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.¹H NMR (500 MHz, DMSO-d₆) δ: 11.94 (s, 1H), 8.62 (d, J=1.7 Hz, 1H), 8.36(d, J=8.2 Hz, 1H), 8.26 (dd, J=1.3, 0.7 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H),7.91 (dd, J=8.2, 1.4 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H).

Step 2: Methyl5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylatewas prepared from methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylateand (2,4-difluorophenyl)(oxan-4-yl)methanol (prepared in route to2-{5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol)according to Step 2 in route to2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.LC/MS (M+H)=535.1; LC/MS RT=1.15 min (Column: Waters Aquity BEH C182.1×50 mm 1.7 u; Mobile Phase A: water with 0.05% TFA; Mobile Phase B:acetonitrile with 0.05% TFA; Temperature: 40° C.; Gradient: 2-98% B over1.5 min; Flow: 0.8 mL/min).

Step 3:2-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-olwas prepared from methyl5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylateaccording to Step 2 in route to2-{6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.Enantiomers A and B were separated using chiral SFC (Column: ChiralcelOD-H preparative column, 30×250 mm, 5 μm; Mobile Phase: 15% methanol inCO₂, 150 bar; Flow: 70 mL/min; Temperature 35° C.). The first elutingenantiomer was defined as Enantiomer A (11.4 mg, 0.0210 mmol, 13%), andthe second eluting enantiomer was defined as Enantiomer B (13.7 mg,0.0250 mmol, 15%). ¹H NMR (DMSO-d₆) δ: 8.35-8.72 (m, 2H), 8.28 (d, J=7.0Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.98 (br. s, 1H), 7.47 (d, J=7.7 Hz,1H), 7.12-7.24 (m, 2H), 5.99 (d, J=11.0 Hz, 1H), 4.02 (br. s., 3H),3.85-3.94 (m, 1H), 3.72 (d, J=8.8 Hz, 1H), 3.34-3.54 (m, 2H), 3.14-3.25(m, 2H), 1.66-1.78 (m, 1H), 1.45-1.66 (m, 6H), 1.28-1.42 (m, 1H),0.74-0.89 (m, 1H); LC/MS (M+H)=535.6; LC/MS RT=1.32 min (Column:Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:waterwith 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Examples 282 & 2832-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1:2-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{5-[(2,4-Difluorophenyl)(oxan-4-yl)methyl]-6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-olwas prepared from previously described starting materials following theroute to2-{5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.Enantiomers A and B were separated using chiral preparatory HPLC(Column: Chiralpak OD 21×250 mm 10 u; Mobile Phase: 13% ethanol inheptane with 0.1% diethylamine; Flow: 15 mL/min). The first elutingenantiomer was defined as Enantiomer A (3.50 mg, 6.33 μmol, 6%), and thesecond eluting enantiomer was defined as Enantiomer B (3.70 mg, 6.70μmol, 6%). ¹H NMR (DMSO-d₆) δ: 8.49-8.56 (m, 1H), 8.22-8.33 (m, 1H),8.07-8.14 (m, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.58-7.68 (m, 1H), 7.10-7.24(m, 2H), 6.17-6.30 (m, 1H), 3.85-3.95 (m, 4H), 3.71-3.83 (m, 1H), 3.25(t, J=11.9 Hz, 1H), 3.17 (d, J=4.8 Hz, 2H), 1.74-1.81 (m, 1H), 1.66 (br.s., 6H), 1.31-1.43 (m, 2H), 0.99-1.09 (m, 1H); LC/MS (M+H)=553.3; LC/MSRT=1.50 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A:10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Example 2842-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylatewas prepared from methyl3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(prepared in route to2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol)and (R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methylmethanesulfonate according to Steps 2 and 3 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole).LC/MS (M+H)=514.3; LC/MS RT=1.71 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 22-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(40.0 mg, 0.0780 mmol, 50%) was prepared from methyl3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylateaccording to Step 2 in route to2-{6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.LC/MS (M+H)=514.3; LC/MS RT=1.36 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 3:2-{5-[(S)-(4-Fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(40.0 mg, 0.0780 mmol) and sodium tert-butoxide (44.9 mg, 0.467 mmol)were stirred in CD₃OD (779 μL) at 80° C. for 16 h. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford2-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(8.40 mg, 0.0160 mmol, 20%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (s, 1H),8.23 (br. s., 1H), 8.12 (d, J=8.1 Hz, 2H), 7.75-7.63 (m, 2H), 7.45 (d,J=8.1 Hz, 1H), 7.16 (t, J=8.6 Hz, 2H), 5.80 (d, J=11.0 Hz, 1H), 3.90 (d,J=5.1 Hz, 1H), 3.74 (d, J=11.0 Hz, 1H), 3.54-3.29 (m, 4H), 3.25 (t,J=11.6 Hz, 1H), 2.30 (s, 3H), 1.69 (d, J=12.5 Hz, 1H), 1.58 (s, 6H),1.30 (d, J=8.8 Hz, 1H), 0.99 (d, J=12.5 Hz, 1H); LC/MS (M+H)=517.3;LC/MS RT=1.36 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile PhaseA: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Example 2852-{5-[(S)-(2-Fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{5-[(S)-(2-Fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol(23.0, 0.0450 mmol, 38%) was prepared according to the proceduresdescribed for2-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.30-8.07 (m, 3H), 7.95 (s,1H), 7.44 (d, J=8.1 Hz, 1H), 7.39-7.26 (m, 2H), 7.11 (t, J=9.4 Hz, 1H),5.98 (d, J=11.4 Hz, 1H), 3.90 (d, J=5.9 Hz, 1H), 3.72 (d, J=11.0 Hz,1H), 3.55-3.32 (m, 3H), 3.27-3.14 (m, 1H), 2.29 (br. s., 3H), 1.74 (d,J=12.8 Hz, 1H), 1.67-1.43 (m, 7H), 1.43-1.25 (m, 1H), 0.81 (d, J=12.1Hz, 1H); LC/MS (M+H)=517.4; LC/MS RT=1.37 min (Column: Phenomenex Luna30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA;Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Examples 286 & 2872-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (5-Methyl-1,2-oxazol-3-yl)(oxan-4-yl)methanol

4-Bromooxane (270 μL, 2.42 mmol) was added drop wise to a stirredsuspension of magnesium (58.9 mg, 2.42 mmol) and one crystal of iodinein THF (1700 μL) at ambient temperature. The reaction mixture wasstirred for 1 h before 5-methyl-1,2-oxazole-3-carbaldehyde (119 μL, 1.28mmol) was added in a single portion. The reaction mixture was thenstirred for 16 h. The reaction mixture was quenched with a minimumamount of saturated aqueous ammonium chloride (5 mL), and the volatileswere removed under reduced pressure. The crude reaction material waspurified using reverse phase preparatory HPLC (TFA/acetonitrile/water).(5-Methyl-1,2-oxazol-3-yl)(oxan-4-yl)methanol (90.9 mg, 0.461 mmol, 36%)was isolated as a colorless oil. LC/MS (M+H)=198.2; LC/MS RT=0.84 min(Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Step 2: (5-Methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl methanesulfonate

(5-Methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl methanesulfonate (119 mg,0.431 mmol, 94%) was prepared from(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methanol according to Step 2 inroute to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.¹H NMR (400 MHz, DMSO-d₆) δ 6.37 (s, 1H), 5.46 (d, J=7.8 Hz, 1H),3.92-3.79 (m, 2H), 3.42-3.18 (m, 2H), 3.16 (s, 3H), 2.42 (s, 3H), 2.12(dtd, J=11.5, 7.6, 3.9 Hz, 1H), 1.70 (d, J=11.8 Hz, 1H), 1.47-1.18 (m,2H), 0.98 (br. s., 1H).

Step 3: Methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylatewas prepared from (5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methylmethanesulfonate and methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(prepared in route to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol)according to Step 3 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.LC/MS (M+H)=501.3; LC/MS RT=1.42 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 4:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olwas prepared from methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylateaccording to Step 3 in route to2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-65% Bover 30 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.Enantiomers A and B were separated using chiral preparatory HPLC(Column: Chiralpak OD 21×250 mm 10 u; Mobile Phase: 10% ethanol inheptane with 0.1% diethylamine; Flow: 15 mL/min). The first elutingenantiomer was defined as Enantiomer A (6.10 mg, 0.0120 mmol, 4%), andthe second eluting enantiomer was defined as Enantiomer B (6.00 mg,0.0120 mmol, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (d, J=1.5 Hz, 1H),8.34 (br. s., 1H), 8.17 (d, J=8.1 Hz, 1H), 8.04 (br. s., 1H), 7.50 (d,J=8.1 Hz, 1H), 6.30 (br. s., 1H), 5.97 (d, J=11.0 Hz, 1H), 4.04 (s, 3H),3.92 (d, J=6.6 Hz, 1H), 3.69 (d, J=8.1 Hz, 1H), 3.41 (t, J=10.8 Hz, 1H),3.19 (q, J=11.9 Hz, 2H), 2.35-2.28 (m, 6H), 1.71-1.59 (m, 1H), 1.56 (s,6H), 1.33-1.15 (m, 2H), 0.86 (d, J=10.3 Hz, 1H); LC/MS (M+H)=501.3;LC/MS RT=1.19 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile PhaseA: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Examples 288-307

The compounds in Table 12 were prepared from commercially available orpreviously described starting materials according to analogousprocedures described for2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,or2-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol:

TABLE 12 HPLC RT HPLC MS Example Structure (min) Method (M + H) 288Enantiomer A

29.60 A 533.3 289 Enantiomer B

36.73 A 533.3 290 Enantiomer B

22.68 B 519.3 291^(A)

2.06 C 527.3 292^(A) Enantiomer A

1.88 D 498.3 293^(A) Enantiomer A

17.94 E 515.3 294^(A) Enantiomer B

25.67 E 515.3 295^(A) Enantiomer A

15.41 E 511.3 296^(A) Enantiomer A

19.86 E 498.4 297^(A) Enantiomer A

12.58 F 531.4 298^(A) Enantiomer B

16.29 F 531.4 299^(A,B) Enantiomer A

18.75 G 502.5 300^(A,B) Enantiomer B

22.33 G 502.5 301^(A) Enantiomer A

12.25 E 511.5 302^(A) Enantiomer B

16.01 E 511.5 303^(A) Enantiomer A

1.44 H 531.4 304^(A) Enantiomer B

1.44 H 531.4 305^(A) Enantiomer B

80.08 I 533.5 306 Enantiomer A

34.43 J 501.5 307 Enantiomer B

39.51 J 501.5

-   -   Footnote A: Final compounds were prepared using methyllithium        according to Step 3 in route to        2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.        Footnote B: (3-Methyl-1,2,4-oxadiazol-5-yl)(oxan-4-yl)methanol        prepared according to Amarasinghe, K. D. D.; et al. Tetrahedron        Lett. 2006, 47, 3629-3631.    -   HPLC Conditions for Table 12: Method A: Column: Chiralcel OD        21×250 mm 10 μm; Mobile Phase: 20:80 ethanol:heptane with 0.1%        diethylamine; Flow: 15 mL/min. Method B: Column: Chiralcel AD-H        preparative column, 30×250 mm, 5 μm; Mobile Phase: 10% methanol        in CO₂, 100 Bar; Flow: 70 mL/min. Method C: Column: Phenomenex        Luna C18 50×2.0 MM 3 u; Mobile Phase A: 10:90 acetonitrile:water        with 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with        0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min;        Flow: 0.8 mL/min. Method D: Column: Phenomenex Luna C18 50×2.0        mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA;        Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;        Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 0.8        mL/min. Method E: Column: Chiralcel OD 21×250 mm 10 μm; Mobile        Phase: 15:85 ethanol:heptane with 0.1% diethylamine; Flow: 15        mL/min. Method F: Column: Chiralcel OD-H preparative column,        30×250 mm, 5 μm; Mobile Phase: 20% methanol in CO₂, 150 Bar;        Flow: 70 mL/min. Method G: Column: Chiralcel OD-H preparative        column, 30×250 mm, 5 μm; Mobile Phase: 15% methanol in CO₂, 150        Bar; Flow: 70 mL/min. Method H: Column: Waters BEH C18, 2.0×50        mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water        with 10 mM ammonium acetate; Mobile Phase B: 95:5        acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°        C.; Gradient: 0% B, 0-100% B over 3 min, then a 0.5-min hold at        100% B; Flow: 1 mL/min. Method I: Column: Chiralpak AD 21×250 mm        10 μm; Mobile Phase: 12:78 ethanol:heptane with 0.1%        diethylamine; Flow: 15 mL/min. Method J: Column: Chiralcel OD-H        preparative column, 30×250 mm, 5 μm; Mobile Phase: 10% methanol        in CO₂, 150 Bar; Flow: 70 mL/min.

Examples 308 & 3092-{5-[(5-Methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylatewas prepared from methyl3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate(prepared in route to2-{5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol)and (5-methyl-1,2-oxazol-3-yl)(oxan-4-yl) methanesulfonate (prepared inStep 2 in route to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol)according to Step 3 in route to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.LC/MS (M+H)=504.3; LC/MS RT=1.43 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 2:2-{5-[(5-Methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{5-[(5-Methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-olwas prepared from methyl5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylateaccording to the procedure described in Step 2 in route to methyl6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indole-7-carboxylate.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% Bover 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford racemic2-{5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.Enantiomers A and B were separated using chiral preparatory HPLC(Column: Chiralcel OD 21×250 mm 10 μm particles; Mobile Phase A: heptanewith 0.1% diethylamine; Mobile Phase B: ethanol; Gradient: 12% B over 41min; Flow: 15 mL/min). The first eluting enantiomer was defined asEnantiomer A (6.60 mg, 0.0130 mmol, 9%), and the second elutingenantiomer was defined as Enantiomer B (6.90 mg, 0.0140 mmol, 9%). ¹HNMR (500 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.32 (br. s., 1H), 8.17 (d, J=8.1Hz, 1H), 8.03 (br. s., 1H), 7.50 (d, J=8.1 Hz, 1H), 6.30 (br. s., 1H),5.97 (d, J=11.0 Hz, 1H), 4.04 (s, 3H), 3.95-3.88 (m, 1H), 3.69 (d, J=9.5Hz, 1H), 3.46-3.32 (m, 1H), 3.26-3.13 (m, 2H), 2.32 (s, 3H), 1.90 (d,J=11.7 Hz, 1H), 1.70-1.59 (m, 1H), 1.56 (s, 6H), 1.33-1.19 (m, 1H), 0.87(d, J=11.0 Hz, 1H); LC/MS (M+H)=504.5; LC/MS RT=1.22 min (Column:Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:waterwith 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Examples 310-329

The compounds in Table 13 were prepared from commercially available orpreviously described starting materials according to analogousprocedures described for2-{5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,2-{8-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,2-{5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,or(1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol.All compounds are homochiral:

TABLE 13 HPLC RT HPLC MS Example Structure (min) Method (M + H) 310Enantiomer A

3.41 A 518.3 311 Enantiomer B

5.71 A 518.3 312 Enantiomer B

80.20 B 534.4 313 Enantiomer A

14.09 C 522.4 314 Enantiomer B

23.94 D 522.4 315 Enantiomer A

18.76 E 518.5 316 Enantiomer B

25.62 E 518.5 317 Enantiomer B

49.19 F 518.3 318 Enantiomer A

9.91 G 568.5 319 Enantiomer B

11.18 G 568.5 320 Enantiomer B

46.73 F 534.3 321 Enantiomer A

81.38 B 534.5 322 Enantiomer B

118.13 B 534.5 323 Enantiomer B

25.91 H 536.6 324^(A) Enantiomer A

29.18 H 536.6 325 Enantiomer A

8.66 I 548.3 326 Enantiomer B

13.68 I 548.3 327 Enantiomer A

11.88 C 508.7 328 Enantiomer B

13.47 C 508.7 329 Diastereomer D

40.44 J 548.7

-   -   Footnote A: Final compounds were prepared using methyllithium        according to Step 3 in route to        2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.    -   HPLC Conditions for Table 13: Method A: Column: Chiralcel OJ-H        preparative column, 30×250 mm, 5 μm; Mobile Phase: 30% methanol        in CO₂, 140 Bar; Flow: 70 mL/min. Method B: Column: Chiralcel OJ        21×250 mm 10 μm; Mobile Phase: 10:90 ethanol:heptane with 0.1%        diethylamine; Flow: 15 mL/min. Method C: Column: Chiralcel OD-H        preparative column, 30×250 mm, 5 μm; Mobile Phase: 15% methanol        in CO₂, 150 Bar; Flow: 70 mL/min. Method D: Column: Chiralcel        AD-H preparative column, 30×250 mm, 5 μm; Mobile Phase: 10%        ethanol in CO₂, 150 Bar; Flow: 70 mL/min. Method E: Column:        Chiralcel OD 21×250 mm 10 μm; Mobile Phase: 15:85        ethanol:heptane with 0.1% diethylamine; Flow: 15 mL/min. Method        F: Column: Chiralpak AD 21×250 mm 10 μm; Mobile Phase: 8:92        ethanol:heptane with 0.1% diethylamine; Flow: 15 mL/min. Method        G: Column: Chiralcel OJ-H preparative column, 30×250 mm, 5 μm;        Mobile Phase: 10% methanol in CO₂, 150 Bar; Flow: 70 mL/min.        Method H: Column: Chiralpak IB preparative column, 30×250 mm, 5        μm; Mobile Phase: 10% methanol in CO₂, 150 Bar; Flow: 70 mL/min.        Method I: Column: Chiralcel OD 21×250 mm 10 μm; Mobile Phase:        25:75 ethanol:heptane with 0.1% diethylamine; Flow: 15 mL/min.        Method J: Column: Lux Cellulose-2 preparative column, 21×250 mm,        5 μm; Mobile Phase: 20% ethanol in CO₂, 150 Bar; Flow: 50        mL/min.

Examples 330 & 3315-{7-Methanesulfonyl-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

Step 1:5-{7-Methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

5-{7-Methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole(233 mg, 0.677 mmol, >100% yield) was prepared from3-bromo-7-methanesulfonyl-5H-pyrido[3,2-b]indole and4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (preparedin route to5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole)according to Step 1 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.66 (d, J=1.5 Hz, 1H),8.51-8.43 (m, 1H), 8.24-8.13 (m, 2H), 7.83 (dd, J=8.2, 1.1 Hz, 1H), 4.03(s, 3H), 3.32 (s, 3H); LC/MS (M+H)=345.3; LC/MS RT=1.05 min (Column:Phenomenex Luna 30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:waterwith 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 2:5-{7-Methanesulfonyl-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole

5-{7-Methanesulfonyl-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazolewas prepared from5-{7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazoleand (5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl methanesulfonate(prepared in route to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol)according to Step 3 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.The crude material was purified via preparative LC/MS with the followingconditions: Column: Chiralcel OD 21×250 mm 10 μm particles; Mobile PhaseA: heptane with 0.1% diethylamine; Mobile Phase B: ethanol; Gradient:12% B over 41 min; Flow: 15 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordracemic5-{7-methanesulfonyl-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.Enantiomers A and B were separated using chiral SFC (Column: ChiralcelOJ-H preparative column, 30×250 mm, 5 μm; Mobile Phase: 20% methanol inCO₂, 150 Bar; Flow: 70 mL/min). The first eluting enantiomer was definedas Enantiomer A (12.1 mg, 0.0230 mmol, 10%), and the second elutingenantiomer was defined as Enantiomer B (12.6 mg, 0.0240 mmol, 10%). ¹HNMR (500 MHz, DMSO-d₆) δ 8.79-8.58 (m, 2H), 8.52 (d, J=8.1 Hz, 2H), 7.90(d, J=8.4 Hz, 1H), 6.38 (br. s., 1H), 6.18 (d, J=11.0 Hz, 1H), 4.06 (s,3H), 3.92 (d, J=8.4 Hz, 1H), 3.68 (d, J=9.5 Hz, 1H), 3.42 (t, J=12.1 Hz,1H), 3.29-3.12 (m, 2H), 2.33 (s, 3H), 1.87 (d, J=12.1 Hz, 1H), 1.68 (d,J=11.7 Hz, 1H), 1.37-1.21 (m, 1H), 0.88-0.76 (m, 1H); LC/MS (M+H)=524.4;LC/MS RT=1.28 min (Column: Phenomenex Luna 30×2.0 mm 3 u; Mobile PhaseA: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 2 min; Flow: 1 mL/min).

Examples 332-340

The compounds in Table 14 were prepared from commercially availablealdehydes according to the procedures described for5-{7-methanesulfonyl-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.All compounds are homochiral:

TABLE 14 HPLC RT HPLC MS Example Y (min) Method (M + H) 332 Enantiomer A

35.36 A 538.5 333 Enantiomer B

47.99 A 538.5 334 Enantiomer B

20.22 B 554.5 335 Enantiomer A

34.53 C 554.5 336 Enantiomer A

16.78 D 550.5 337 Enantiomer A

67.13 E 534.0 338 Enantiomer B

78.46 F 534.3 339 Enantiomer A

51.77 G 554.5 340 Enantiomer B

65.34 G 554.5

HPLC Conditions for Table 14: Method A: Column: Chiralpak AD 21×250 mm10 μm; Mobile Phase: 18:82 ethanol:heptane with 0.1% diethylamine; Flow:15 mL/min. Method B: Column: Chiralpak AD 21×250 mm 10 μm; Mobile Phase:25:75 ethanol:heptane with 0.1% diethylamine; Flow: 15 mL/min. Method C:Column: Chiralpak AD-H preparative column, 30×250 mm, 5 μm; MobilePhase: 10% methanol in CO₂, 100 Bar; Flow: 70 mL/min. Method D: Column:Chiralcel OD 21×250 mm 10 μm; Mobile Phase: 30:70 ethanol:heptane with0.1% diethylamine; Flow: 15 mL/min. Method E: Column: Chiralpak AD21×250 mm 10 μm; Mobile Phase: 10:90 ethanol:heptane with 0.1%diethylamine; Flow: 15 mL/min. Method F: Column: Chiralpak AD 21×250 mm10 μm; Mobile Phase: 12:88 ethanol:heptane with 0.1% diethylamine; Flow:15 mL/min. Method G: Column: Chiralpak AD 21×250 mm 10 μm; Mobile Phase:15:85 ethanol:heptane with 0.1% diethylamine; Flow: 15 mL/min.

Examples 341 & 3422-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1,3-dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (1,3-Dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methanol

(1,3-Dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methanol was prepared accordingto Step 1 in route to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.LC/MS (M+H)=211.2; LC/MS RT=0.92 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 2: Methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1,3-dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(prepared in route to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,92.0 mg, 0.285 mmol), (1,3-dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methanol(90.0 mg, 0.428 mmol), and 2-(trimethylphosphoranylidene)acetonitrile(856 μL, 0.428 mmol) were stirred in toluene (2850 μL) at 85° C. underN₂ (g) for 16 h. The volatiles were removed under reduced pressure, andthe reaction material was used without purification. LC/MS (M+H)=514.3;LC/MS RT=0.98 min (Column: Waters Aquity BEH C18 2.1×50 mm 1.7 u; MobilePhase A: water with 0.05% TFA; Mobile Phase B: acetonitrile with 0.05%TFA; Temperature: 40° C.; Gradient: 2-98% B over 1.5 min; Flow: 0.8mL/min).

Step 3:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1,3-dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1,3-dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olwas prepared from methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1,3-dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylateaccording to Step 3 in route to2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-45% Bover 30 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford racemic2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1,3-dimethyl-1H-pyrazol-5-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.Enantiomers A and B were separated using chiral SFC (Column: ChiralPakIC-H, 30×250 mm, 5 μm; Mobile Phase: 40% methanol in CO₂, 150 bar; Flow:70 mL/min; Temperature 35° C.). The first eluting enantiomer was definedas Enantiomer A (2.10 mg, 3.43 μmol, 2%), and the second elutingenantiomer was defined as Enantiomer B (3.10 mg, 5.79 μmol, 3%). ¹H NMR(500 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.41-8.01 (m, 2H), 7.52 (d, J=7.7 Hz,1H), 7.39 (d, J=4.4 Hz, 1H), 6.84 (br. s., 1H), 5.96 (d, J=11.0 Hz, 1H),4.01 (br. s., 3H), 3.91 (br. s., 1H), 3.68 (d, J=9.9 Hz, 1H), 3.43 (br.s., 1H), 3.21-3.05 (m, 2H), 2.30 (br. s., 3H), 2.14 (s, 3H), 1.97-1.82(m, 1H), 1.72-1.46 (m, 7H), 1.31-1.21 (m, 3H), 0.89-0.77 (m, 1H), 0.72(d, J=10.6 Hz, 1H); LC/MS (M+H)=514.3; LC/MS RT=0.87 min (Column: WatersAquity BEH C18 2.1×50 mm 1.7 u; Mobile Phase A: water with 0.05% TFA;Mobile Phase B: acetonitrile with 0.05% TFA; Temperature: 40° C.;Gradient: 2-98% B over 1.5 min; Flow: 0.8 mL/min).

Examples 343 & 3442-{5-[(3-Fluoropyridin-4-yl)(oxan-4-yl)(²H)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: (3-Fluoropyridin-4-yl)(oxan-4-yl)methanol

(3-Fluoropyridin-4-yl)(oxan-4-yl)methanol (301 mg, 1.42 mmol, 47%) wasprepared from 3-fluoropyridine-4-carbaldehyde according to Step 1 inroute to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.LC/MS (M+H)=212.2; LC/MS RT=0.40 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 2: (3-Fluoropyridin-4-yl)(oxan-4-yl)methyl methanesulfonate

(3-Fluoropyridin-4-yl)(oxan-4-yl)methyl methanesulfonate was preparedfrom (3-fluoropyridin-4-yl)(oxan-4-yl)methanol according to Step 2 inroute to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.

Step 3: Methyl3-(dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl3-(dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylatewas prepared from methyl3-(dimethyl-1,2-oxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(prepared in route to2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol)and (3-fluoropyridin-4-yl)(oxan-4-yl)methyl methanesulfonate accordingto Step 3 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.LC/MS (M+H)=515.7; LC/MS RT=1.46 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 4:3-(Dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olwas prepared from methyl3-(dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylateaccording to Step 3 in route to2-{3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.LC/MS (M+H)=515.3; LC/MS RT=1.18 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 5:2-{5-[(3-Fluoropyridin-4-yl)(oxan-4-yl)(²H)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{5-[(3-Fluoropyridin-4-yl)(oxan-4-yl)(²H)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-olwas prepared from2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olaccording to Step 3 in route to2-{5-[(2,4-difluorophenyl)(oxan-4-yl)methyl]-6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% Bover 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford racemic2-{5-[(3-fluoropyridin-4-yl)(oxan-4-yl)(²H)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.Enantiomers A and B were separated using chiral SFC (Column: ChiralcelOD-H preparative column, 30×250 mm, Sum; Mobile Phase: 20% methanol inCO₂, 150 bar; Flow: 70 mL/min; Temperature 35° C.). The first elutingenantiomer was defined as Enantiomer A (1.90 mg, 3.66 μmol, 2%), and thesecond eluting enantiomer was defined as Enantiomer B (2.10 mg, 3.89μmol, 2%). LC/MS (M+H)=519.3; LC/MS RT=1.18 min (Column: Phenomenex Luna30×2.0 mm 3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA;Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40°C.; Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Examples 345 & 3462-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1:2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

2-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olwas analogously prepared according to Steps 1-4 in route to2-{5-[(3-fluoropyridin-4-yl)(oxan-4-yl)(²H)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% Bover 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford racemic2-{5-[(3-fluoropyridin-4-yl)(oxan-4-yl)(²H)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.Enantiomers A and B were separated using chiral preparatory HPLC(Column: Chiralcel OJ 21×250 mm 10 μm particles; Mobile Phase A: heptanewith 0.1% diethylamine; Mobile Phase B: ethanol; Gradient: 8% B over 110min; Flow: 15 mL/min). The first eluting enantiomer was defined asEnantiomer A (10.9 mg, 0.0210 mmol, 21%), and the second elutingenantiomer was defined as Enantiomer B (9.00 mg, 0.0170 mmol, 17%). ¹HNMR (DMSO-d₆) δ: 8.60 (br. s., 1H), 8.24-8.53 (m, 2H), 7.99-8.14 (m,2H), 7.68 (d, J=8.8 Hz, 1H), 7.40-7.52 (m, 2H), 6.14 (d, J=10.6 Hz, 1H),3.87 (d, J=10.3 Hz, 1H), 3.69 (d, J=10.3 Hz, 1H), 3.44-3.52 (m, 4H),3.18 (t, J=11.7 Hz, 1H), 2.35 (br. s, 3H), 1.71 (br. s., 1H), 1.43-1.64(m, 8H), 1.26-1.38 (m, 1H), 0.70 (d, J=12.8 Hz, 1H); LC/MS (M+H)=515.5;LC/MS RT=2.50 min (Column: Phenomenex Luna C18 50×2.0 mm 3 u; MobilePhase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100%B over 4 min; Flow: 0.8 mL/min).

Examples 347 & 3482-{5-[(3-Fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-bromo-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate

Methyl3-bromo-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylatewas prepared from methyl3-bromo-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (prepared inroute to2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(2-fluorophenyl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol)and (3-fluoropyridin-4-yl)(oxan-4-yl)methyl methanesulfonate (preparedin route to2-{5-[(3-fluoropyridin-4-yl)(oxan-4-yl)(²H)methyl]-3-[5-(²H₃)methyl-3-methyl-1,2-oxazol-4-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol)according to Step 3 in route to5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.LC/MS (M+H)=528.2; LC/MS RT=2.24 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 2:2-{3-Bromo-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{3-Bromo-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (22.3 mg, 0.0420 mmol, 12%) was prepared frommethyl3-bromo-5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-5H-pyrido[3,2-b]indole-7-carboxylateaccording to Step 2 in route to2-{6-fluoro-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.LC/MS (M+H)=528.2; LC/MS RT=1.83 min (Column: Phenomenex Luna 30×2.0 mm3 u; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; MobilePhase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 3:2-{5-[(3-Fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{5-[(3-Fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-olwas prepared according to Step 3 in route to5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methyl-1-methyl-1H-1,2,3-triazole.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile PhaseB: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient:10-50% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford racemic2-{5-[(3-fluoropyridin-4-yl)(oxan-4-yl)methyl]-9-methoxy-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.Enantiomers A and B were separated using chiral preparatory HPLC(Column: Chiralcel OJ 21×250 mm 10 μm particles; Mobile Phase A: heptanewith 0.1% diethylamine; Mobile Phase B: ethanol; Gradient: 30% B over 30min; Flow: 15 mL/min). The first eluting enantiomer was defined asEnantiomer A (3.90 mg, 7.12 μmol, 17%), and the second elutingenantiomer was defined as Enantiomer B (4.00 mg, 7.30 μmol, 18%). LC/MS(M+H)=548.3; LC/MS RT=1.11 min (Column: Phenomenex Luna 30×2.0 mm 3 u;Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B:90:10 acetonitrile:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 2 min; Flow: 1 mL/min).

Example 3515-[7-(2-Fluoropropan-2-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

To a cold (−78° C.), stirred solution of(S)-2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(43.2 mg, 0.0870 mmol) in dichloromethane (9.7 mL) under N₂ was addeddiethylaminosulfur trifluoride (0.050 mL, 0.378 mmol), the reactionmixture was stirred for 3 h, warmed to 0° C., and stirred for 30 min. Tothe reaction was added sat. aq. NaHCO₃ (2 mL), and the reaction waswarmed to room temperature. The mixture was diluted with DCM, washedwith H₂O, dried (MgSO₄), filtered, and concentrated. The crude materialwas purified via preparative LC/MS (Column: Waters XBridge C18, 19×200mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 25-100% B over 25 min, then a 5-min hold at100% B; Flow: 20 mL/min). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give(5-[7-(2-fluoropropan-2-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole(17.7 mg, 40%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.43 (br. s.,1H), 8.22 (d, J=8.1 Hz, 1H), 8.09 (br. s., 1H), 7.66 (d, J=7.4 Hz, 2H),7.40 (d, J=8.1 Hz, 1H), 7.28-7.36 (m, 2H), 7.21-7.27 (m, 1H), 5.89 (d,J=11.1 Hz, 1H), 4.00 (s, 3H), 3.84-3.93 (m, 1H), 3.73 (d, J=8.8 Hz, 1H),3.48 (t, J=11.1 Hz, 1H), 3.37 (br. s., 1H), 3.25 (t, J=11.4 Hz, 1H),2.29 (s, 3H), 1.75-1.88 (m, 6H), 1.70 (d, J=12.8 Hz, 1H), 1.52-1.65 (m,1H), 1.25-1.40 (m, 1H), 0.98 (d, J=12.5 Hz, 1H); HPLC: RT=1.84 min(Column: Waters Acquity UPLC BEH C₁₈, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm); MS (ES): m/z=498[M+1]⁺.

Example 3525-[6-Fluoro-7-(2-fluoropropan-2-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

To a cold (−78° C.), stirred solution of(S)-2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(50.4 mg, 0.0980 mmol) in dichloromethane (4.9 mL) under N₂ (g) wasadded diethylaminosulfur trifluoride (0.050 mL, 0.378 mmol). Thereaction was stirred at −78° C. for 90 min. The reaction was placed in a0° C. bath and stirred for 40 min. To the reaction was added sat. aq.NaHCO₃ (2 mL), and the reaction was warmed to room temperature. Themixture was diluted with DCM, washed with H₂O, dried (MgSO₄), filtered,and concentrated. The crude material was purified via preparative LC/MS(Column: Waters XBridge C₁₈, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-95% Bover 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give(5-[6-fluoro-7-(2-fluoropropan-2-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole(20.0 mg, 40%)): ¹H NMR appears to be a mixture of atropisomers: ¹H NMR(500 MHz, DMSO-d₆) δ 8.25 (br s, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.94 (s,1H), 7.64 (br s, 3H), 7.43 (br s, 2H), 7.34 (br s, 4H), 7.26 (br d,J=7.1 Hz, 2H), 6.00-5.89 (m, 2H), 4.00-3.82 (m, 7H), 3.76 (br d, J=9.1Hz, 2H), 3.54-3.43 (m, 1H), 3.41 (br d, J=7.4 Hz, 1H), 3.27 (br t,J=11.3 Hz, 2H), 2.22 (br s, 6H), 2.01-1.69 (m, 14H), 1.34 (br d, J=10.4Hz, 4H), 1.06 (br d, J=12.8 Hz, 2H); HPLC: RT=2.13 min (Column: WatersAcquity UPLC BEH C₁₈, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min; Detection: UV at 220 nm); MS (ES): m/z=516 [M+1]⁺.

Example 3532-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-8-methoxy-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a 100 mL round-bottomed flask equipped with a stir bar was addedmethyl 4-bromo-2-methoxybenzoate (1.79 g, 7.30 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.78 g,10.9 mmol), PdCl₂(dppf) (0.267 g, 0.365 mmol), and potassium acetate(2.15 g, 21.9 mmol) at ambient temperature. The flask was sealed with aseptum, dioxane (36.5 ml) was added, and the atmosphere was purged withN₂ (g). The reaction was then heated to 90° C. with stirring for 3 h andcooled to room temperature. The reaction was concentrated, the residuewas dissolved in EtOAc and washed with 1M aq. HCl and sat. aq. NaCl. Theorganics were dried (Na₂SO₄), filtered, and concentrated. The residuewas purified by silica gel column chromatography (Teledyne ISCOCombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH₂Cl₂/EtOAcover 15 column volumes, RediSep SiO₂ 80 g, loaded as DCM solution) toafford (methyl2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.87g, 88%) as a tan solid: ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=7.7 Hz,1H), 7.42 (dd, J=0.7, 0.9 Hz, 1H), 7.39 (s, 1H), 3.96 (s, 3H), 3.90 (s,3H), 1.36 (s, 12H); HPLC: RT=1.284 min (Waters Acquity BEH C₁₈ 1.7 um2.0×50 mm, CH₃CN/H₂O/0.1% TFA, 1.5 min gradient, wavelength=254 nm); MS(ES): m/z=293 [M+1]⁺.

Step 2: Methyl 3-bromo-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylateand methyl 3-bromo-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate

To a stirred solution of methyl2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.30g, 4.43 mmol), 2,5-dibromo-3-nitropyridine (1.04 g, 3.69 mmol), andPdCl₂(dppf) (0.140 g, 0.191 mmol) in THF (37 mL) was added tripotassiumphosphate (3M in H₂O, 3.7 mL, 11.1 mmol), purged with N₂ (g), and thereaction was heated to 75° C. with stirring for 30 min, cooled to roomtemperature, partially concentrated, diluted with EtOAc, washed withH₂O, sat. aq. NaCl, and dried over sodium sulfate. The solids werefiltered away, and the volatiles were concentrated in vacuo. The residuewas purified by silica gel column chromatography (Teledyne ISCOCombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH₂Cl₂/EtOAcover 15 column volumes, RediSep SiO₂ 120 g, loaded as DCM solution) toafford a mixture of the mono- and bis-coupled products (1.04 g) as apale-yellow solid: HPLC for major product: RT=1.212 min (Waters AcquityBEH C₁₈ 1.7 um 2.0×50 mm, CH₃CN/H₂O/0.1% TFA, 1.5 min gradient,wavelength=254 nm); MS (ES): m/z=367/369 Br⁷⁹/Br⁸¹ [M+1]⁺.

In a 100 mL RB flask was added the mixture above (1.04 g) and1,2-bis(diphenylphosphino)ethane (1.27 g, 3.19 mmol) in1,2-dichlorobenzene (12 mL), and the flask was heated in a pre-heatedheating block at 170° C. for 90 min, then cooled to room temperature.The mixture was poured into 150 mL hexanes, the solid was collected byfiltration, washed with hexanes, and air dried. The residue was purifiedby silica gel column chromatography (Teledyne ISCO CombiFlash Rf,gradient of 0% to 100% using solvent A/B=hexanes/EtOAc over 15 columnvolumes, RediSep SiO₂ 220 g Gold). The clean fractions were set aside,and the mixed fractions resubjected to flash chromatography (TeledyneISCO CombiFlash Rf, gradient of 0% to 30% using solvent A/B=CH₂Cl₂/EtOAcover 19 column volumes, RediSep SiO₂ 12 g Gold). Two regioisomers wereobtained: (methyl 3-bromo-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(339.7 mg, 36%)) as a cream solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s,1H), 8.59 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.1 Hz,1H), 7.61 (d, J=8.1 Hz, 1H), 4.01 (s, 3H), 3.90 (s, 3H); HPLC: RT=0.97min (Waters Acquity BEH C18 1.7 um 2.0×50 mm, CH₃CN/H₂O/0.05% TFA, 1 mingradient, wavelength=220 nm); MS (ES): m/z=335/337 Br⁷⁹/Br⁸¹ [M+1]⁺ and(methyl 3-bromo-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (322 mg,0.962 mmol, 34%)) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.55(s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.87 (s, 1H),7.80 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H); HPLC: RT=0.90 min (WatersAcquity BEH C₁₈ 1.7 um 2.0×50 mm, CH₃CN/H₂O/0.05% TFA, 1 min gradient,wavelength=220 nm); MS (ES): m/z=335/337 Br⁷⁹/Br⁸¹ [M+1]⁺.

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate

In a 50 mL RB flask was added a mixture of methyl3-bromo-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (322 mg, 0.962mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (533 mg, 1.38mmol) and TEA (0.270 mL, 1.94 mmol) in DMF (19 mL), and the mixture waspurged by bubbling nitrogen through the solution. While purging,copper(I) iodide (41.4 mg, 0.217 mmol) and Pd(Ph₃P)₄ (69.5 mg, 0.0600mmol) were added, the flask fitted with a septum, and heated in aheating block at 95° C. with stirring overnight. The reaction cooled toroom temperature and concentrated, the residue was dissolved in EtOAc,washed with H₂O, sat. aq. NaCl, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was dissolved in MeOH/acetone, SiO₂(6 g) was added, and the volatiles removed in vacuo then dried undervacuum. The material was then purified by silica gel columnchromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100%using solvent A/B=CH₂Cl₂/acetone over 15 column volumes, RediSep SiO₂ 40g). Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(167.3 mg, 50%) was obtained as a yellow solid: ¹H NMR (400 MHz,DMSO-d₆) δ 11.62 (s, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.07 (d, J=2.0 Hz,1H), 7.90 (s, 1H), 7.86 (s, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.86 (s,3H), 2.30 (s, 3H); HPLC: RT=0.917 min (Waters Acquity BEH C₁₈ 1.7 um2.0×50 mm, CH₃CN/H₂O/0.1% TFA, 1.5 min gradient, wavelength=254 nm); MS(ES): m/z=352 [M+1]⁺.

Step 4: (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate

To a cool (0° C.), stirred suspension of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(89.6 mg, 0.255 mmol),(R)-(4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (110 mg, 0.522mmol) and triphenylphosphine (108 mg, 0.413 mmol) in toluene (5.2 mL)under N₂ (g) was added dropwise over 1 min via syringe DIAD (0.100 mL,0.514 mmol), the solution stirred for 5 min, then removed from the icebath and stirred at room temperature overnight. THF (5 mL) was added,and stirring continued overnight. The reaction was concentrated in vacuoand dried under vacuum. The residue was purified by silica gel columnchromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 30% usingsolvent A/B=CH₂Cl₂/MeOH over 20 column volumes, RediSep SiO₂ 40 g,loaded as DCM solution). The product was repurified by silica gel columnchromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100%using solvent A/B=hexanes/EtOAc over 12 column volumes, RediSep SiO₂ 12g, loaded as DCM solution, then solvents changed to CH₂Cl₂:MeOH,gradient of 0% to 10% over 12 column volumes. (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(36.0 mg, 26%) was obtained as a cream solid: ¹H NMR (400 MHz, CDCl₃) δ8.47 (d, J=1.8 Hz, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.58 (d, J=1.5 Hz,1H), 7.42 (dd, J=5.2, 8.7 Hz, 2H), 7.05 (t, J=8.6 Hz, 2H), 5.46 (d,J=10.6 Hz, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 3.99 (br dd, J=2.6, 3.7 Hz,1H), 3.94 (s, 3H), 3.91-3.86 (m, 1H), 3.59-3.48 (m, 1H), 3.41-3.30 (m,1H), 3.11-2.96 (m, 1H), 2.32 (s, 3H), 1.95 (br d, J=13.2 Hz, 1H),1.67-1.58 (m, 1H), 1.50-1.36 (m, 1H), 1.13 (br d, J=12.8 Hz, 1H); HPLC:RT=1.125 min (Waters Acquity BEH C₁₈ 1.7 um 2.0×50 mm, CH₃CN/H₂O/0.1%TFA, 1.5 min gradient, wavelength=254 nm); MS (ES): m/z=544 [M+1]⁺.

Step 5:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-8-methoxy-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

To a cold (−78° C.), stirred solution of (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(36.0 mg, 0.0660 mmol) in THF (1.3 mL) under N₂ (g) was addedmethylmagnesium bromide (3M in Et₂O, 0.330 mL, 0.990 mmol). After 20min, the reaction was warmed to −15° C. (ice/MeOH) for 10 min, then thereaction was quenched with sat. aq. NH₄Cl, diluted with EtOAc, theorganic phase was separated, washed with sat. aq. NaCl then dried oversodium sulfate, filtered, and concentrated. The crude material waspurified via preparative LC/MS (Column: Waters XBridge C₁₈, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 15-50% B over 25 min, then a 5-min holdat 50% B; Flow: 20 mL/min). Fractions containing the desired productwere combined and dried via centrifugal evaporation to give2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-8-methoxy-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(22.8 mg, 60%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.35 (br s,2H), 8.19 (br s, 1H), 7.71 (s, 1H), 7.70-7.63 (m, 2H), 7.15 (br t, J=8.6Hz, 2H), 5.67 (br d, J=11.1 Hz, 1H), 4.00 (br s, 3H), 3.92 (s, 3H), 3.88(br d, J=7.7 Hz, 1H), 3.73 (br d, J=9.8 Hz, 1H), 3.50-3.37 (m, 1H), 3.25(br t, J=11.1 Hz, 1H), 2.29 (s, 3H), 1.69-1.62 (m, 2H), 1.60 (br d,J=12.8 Hz, 5H), 1.54-1.43 (m, 1H), 1.35-1.20 (m, 1H), 0.98 (br d, J=12.5Hz, 1H); HPLC: RT=1.52 min (Column: Waters Acquity UPLC BEH C₁₈, 2.1×50mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min,then a 0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220nm); MS (ES): m/z=544 [M+1]⁺.

Example 3542-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a cool (0° C.), stirred suspension of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(39.6 mg, 0.113 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(46.6 mg, 0.242 mmol), and triphenylphosphine (62.1 mg, 0.237 mmol) inTHF (2.3 mL) under N₂ (g) was added dropwise over 1 min via syringe DIAD(0.0500 mL, 0.257 mmol). The suspension dissolved quickly, and theyellow solution was allowed to warm to room temperature and stirredovernight. The reaction was concentrated and dried under vacuumovernight. The residue was purified by silica gel column chromatography(Teledyne ISCO CombiFlash Rf, gradient of 0% to 7% using solventA/B=CH₂Cl₂/MeOH over 30 column volumes, RediSep SiO₂ 24 g, loaded as DCMsolution). (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(29.2 mg, 50%) was isolated as a pale yellow film. HPLC: RT=1.111 min(Waters Acquity BEH C₁₈ 1.7 um 2.0×50 mm, CH₃CN/H₂O/0.1% TFA, 1.5 mingradient, wavelength=254 nm); MS (ES): m/z=526 [M+1]⁺.

Step 2:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

To a cold (−78° C.), stirred solution of (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(29.2 mg, 0.0560 mmol) in THF (1.1 mL) under N₂ (g) was addedmethylmagnesium bromide (3M in Et₂O, 296 μl, 0.889 mmol). After 15 min,the reaction was placed in an ice-water bath and stirred for 20 min. Thereaction was quenched with sat. aq. NH₄Cl (5 mL), diluted with EtOAc,and the organic phase was separated and concentrated. The crude materialwas purified via preparative LC/MS (Column: XBridge C₁₈, 19×250 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 20-85% B over 25 min, then a 5-min hold at 100% B;Flow: 20 mL/min). Fractions containing the desired product were combinedand dried via centrifugal evaporation to give2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-methoxy-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(14.3 mg, 49%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.37 (br s,1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.71 (s, 1H), 7.63 (br d, J=7.7 Hz,2H), 7.36-7.29 (m, 2H), 7.27-7.20 (m, 1H), 5.65 (br d, J=11.1 Hz, 1H),3.99 (s, 3H), 3.91 (s, 3H), 3.87 (br d, J=9.8 Hz, 1H), 3.72 (br d, J=8.8Hz, 1H), 3.52 (br s, 1H), 3.44 (br t, J=11.3 Hz, 1H), 3.35 (br s, 1H),3.26 (br t, J=11.3 Hz, 1H), 2.28 (s, 3H), 1.67 (br d, J=12.5 Hz, 1H),1.60 (br d, J=14.1 Hz, 6H), 1.53-1.42 (m, 1H), 1.35-1.23 (m, 1H), 0.98(br d, J=12.5 Hz, 1H); HPLC: RT=1.56 min (Column: Waters Acquity UPLCBEH C₁₈, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow:1.11 mL/min; Detection: UV at 220 nm); MS (ES): m/z=526 [M+l]⁺.

Example 3552-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate

In a 50 mL RB Flask was added a mixture of methyl3-bromo-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (340 mg, 1.01mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (603 mg, 1.56mmol) and TEA (0.290 mL, 2.08 mmol) in DMF (21 mL), and the mixture waspurged under a nitrogen stream. While purging, was added copper(I)iodide (39.0 mg, 0.205 mmol) and Pd(Ph₃P)₄ (75.1 mg, 0.0650 mmol), andthe vial was capped and heated in a heating block at 95° C. withstirring for 40 h. The reaction was cooled to room temperature, SiO₂ (5g) was added, the volatiles removed under reduced pressure. The materialwas then purified by silica gel column chromatography (Teledyne ISCOCombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH₂Cl₂/acetoneover 20 column volumes, RediSep SiO₂ 40 g). Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(304 mg, 85%) was isolated as a yellow solid: HPLC: RT=0.948 min (WatersAcquity BEH C₁₈ 1.7 um 2.0×50 mm, CH₃CN/H₂O/0.1% TFA, 1.5 min gradient,wavelength=254 nm); MS (ES): m/z=352 [M+1]⁺.

Step 2: (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a cool, stirred suspension of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate(40.5 mg, 0.115 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol(47.1 mg, 0.245 mmol), and triphenylphosphine (60.2 mg, 0.230 mmol) inTHF (2.4 mL) under N₂ (g) was added dropwise over 1 min via syringe DIAD(0.0500 mL, 0.257 mmol). The suspension dissolved quickly, and theyellow solution was allowed to warm to room temperature and stirredovernight. The reaction was concentrated and dried under vacuumovernight. The residue was purified by silica gel column chromatography(Teledyne ISCO CombiFlash Rf, gradient of 0% to 7% using solventA/B=CH₂Cl₂/MeOH over 30 column volumes, RediSep SiO₂ 24 g, loaded as DCMsolution). (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(53.0 mg, 87%) was isolated as a pale-yellow film: HPLC: RT=1.179 min(Waters Acquity BEH C₁₈ 1.7 um 2.0×50 mm, CH₃CN/H₂O/0.1% TFA, 1.5 mingradient, wavelength=254 nm); MS (ES): m/z=526 [M+1]⁺.

Step 3:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

To a cold (−78° C.), stirred solution of (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(53.0 mg, 0.101 mmol) in THF (2017 μl) under N₂ (g) was addedmethylmagnesium bromide (3M in Et₂O, 538 μl, 1.61 mmol), the reactionwas stirred for 30 min before it was allowed to warm to 0° C., andstirred for 15 min before it was quenched with sat. aq. NH₄Cl (5 mL).The reaction mixture was diluted with EtOAc, the organic phase wasseparated, and the volatiles removed. The crude material was purifiedvia preparative LC/MS (Column: Waters XBridge Shield RP₁₈, 19×250 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 20-75% B over 25 min, then a 5-min hold at100% B; Flow: 20 mL/min). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(8.90 mg, 17%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.17 (s, 1H),7.95 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.51 (brd, J=7.4 Hz, 2H), 7.25-7.20 (m, 2H), 7.19-7.14 (m, 1H), 6.15 (br d,J=11.1 Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.83 (br t, J=12.3 Hz, 2H),3.55-3.40 (m, 2H), 2.24 (s, 3H), 1.71 (s, 3H), 1.69 (s, 3H), 1.61 (br d,J=12.5 Hz, 1H), 1.54 (br d, J=9.4 Hz, 1H), 1.48-1.37 (m, 2H); HPLC:RT=1.56 min (Column: Waters Acquity UPLC BEH C₁₈, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm); MS(ES): m/z=526 [M+1]¹.

Example 356[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-6-yl]methanol

Step 1:5-(Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2-benzofuran-1-one

In a 100 ml, round-bottomed flask was added5-bromoisobenzofuran-1(3H)-one (1.00 g, 4.69 mmol),bis(pinacolato)diboron (1.31 g, 5.16 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct(0.383 g, 0.469 mmol), and potassium acetate (1.15 g, 11.7 mmol) indioxane (20 mL) to give a suspension. The flask was equipped with areflux condenser and heated to 80° C. with stirring under nitrogen for16 h. The reaction was partitioned between ethyl acetate (100 mL) andwater (50 mL), and the organic layer was dried with Na₂SO₄, filtered,and concentrated. The reaction mixture was purified using ISCO silicagel chromatography (40 g column, gradient from 0% to 100% EtOAc/hexanes)to give the title compound (0.695 g, 57%). ¹H NMR (400 MHz, DMSO-d₆) δ7.97 (s, 1H), 7.85 (s, 2H), 5.43 (s, 2H), 1.33 (s, 12H) HPLC RT=0.76 min(Column: Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Step 2: 5-(5-Bromo-3-nitropyridin-2-yl)-1,3-dihydro-2-benzofuran-1-one

Following a procedure analogous to that described for methyl4-(5-bromo-3-nitropyridin-2-yl)benzoate,5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2-benzofuran-1-one(695 mg, 2.67 mmol) was converted to the title compound, which waspurified using ISCO silica gel chromatography (24 g column, gradientfrom 0% to 100% EtOAc/hexanes) to give 568 mg (70%). ¹H NMR (400 MHz,DMSO-d₆) δ 9.17 (d, J=2.0 Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 7.97 (d,J=7.9 Hz, 1H), 7.90-7.86 (m, 1H), 7.75-7.69 (m, 1H), 5.50 (s, 2H). LCMS(M+H)=335; HPLC RT=1.12 min (Column: Waters Acquity BEH C182.0×50 mm;Mobile Phase A: 10:90 ACN:water with 0.1% TFA; Mobile Phase B: 90:10ACN:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over1.5 min; Flow: 1 mL/min).

Step 3: 8-Bromo-1H-furo[3,4-g]pyrido[3,2-b]indol-3(10H)-one

Following a procedure analogous to that described for methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate,5-(5-bromo-3-nitropyridin-2-yl)-1,3-dihydro-2-benzofuran-1-one (568 mg,1.70 mmol) was converted to the title compound, which was precipitatedfrom the reaction mixture using DCM to give 287 mg (56%). ¹H NMR (400MHz, DMSO-d₆) δ 8.66 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.37 (d,J=8.1 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 5.69 (s, 2H). LCMS (M+H)=303;HPLC RT=1.05 min (Column: Waters Acquity BEH C182.0×50 mm; Mobile PhaseA: 10:90 ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1mL/min).

Step 4:(S)-8-Bromo-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-furo[3,4-g]pyrido[3,2-b]indol-3(10H)-one

Following a procedure analogous to that described for methyl3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate,8-bromo-1H-furo[3,4-g]pyrido[3,2-b]indol-3(10H)-one (215 mg, 0.710 mmol)and phenyl(tetrahydro-2H-pyran-4-yl)methanol (363 mg, 0.890 mmol) wereconverted to the title compound (248 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆)δ 8.65 (s, 1H), 8.42 (d, J=8.1 Hz, 2H), 7.78 (d, J=7.9 Hz, 1H), 7.36 (d,J=8.8 Hz, 2H), 7.33-7.27 (m, 3H), 5.76 (s, 2H), 3.95-3.85 (m, 2H), 3.71(d, J=11.0 Hz, 2H), 3.62-3.43 (m, 3H), 1.76 (br. s., 1H), 1.65-1.53 (m,1H), 1.41-1.30 (m, 1H). LCMS (M+H)=477; HPLC RT=1.32 min (Column: WatersAcquity BEH C182.0×50 mm; Mobile Phase A: 10:90 ACN:water with 0.1% TFA;Mobile Phase B: 90:10 ACN:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Step 5:(S)-8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-furo[3,4-g]pyrido[3,2-b]indol-3(10H)-one

Following a procedure analogous to that described for the alternatesynthesis of methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,(S)-8-bromo-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-furo[3,4-g]pyrido[3,2-b]indol-3(10H)-one(248 mg, 0.520 mmol) was converted to the title compound (159 mg, 62%).¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=8.1 Hz, 1H), 8.36 (br. s., 1H),7.80 (d, J=8.1 Hz, 1H), 7.72 (d, J=7.0 Hz, 2H), 7.40-7.25 (m, 4H), 5.21(d, J=11.2 Hz, 1H), 3.94 (s, 3H), 3.91 (br. s., 1H), 3.73 (d, J=9.2 Hz,1H), 3.56-3.42 (m, 2H), 3.26 (t, J=10.8 Hz, 1H), 2.25 (s, 4H), 1.78 (d,J=13.2 Hz, 1H), 1.60 (d, J=8.4 Hz, 1H), 1.48-1.36 (m, 1H), 1.25 (d,J=2.4 Hz, 1H). LCMS (M+H)=494; HPLC RT=1.08 min (Column: Waters AcquityBEH C182.0×50 mm; Mobile Phase A: 10:90 ACN:water with 0.1% TFA; MobilePhase B: 90:10 ACN:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 1.5 min; Flow: 1 mL/min).

Step 6:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-(hydroxymethyl)-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described for2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,using(S)-8-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-furo[3,4-g]pyrido[3,2-b]indol-3(10H)-one(15.0 mg, 0.0300 mmol) was converted to the title compound (3.10 mg,20%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.14 (d, J=8.4 Hz, 1H),7.89 (s, 1H), 7.63 (d, J=7.7 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.31 (t,J=7.6 Hz, 2H), 7.25-7.17 (m, 1H), 6.65 (d, J=10.8 Hz, 1H), 5.52 (d,J=10.4 Hz, 1H), 5.48 (s, 1H), 5.35 (d, J=8.1 Hz, 1H), 5.26 (t, J=4.4 Hz,1H), 3.90 (d, J=11.8 Hz, 1H), 3.82 (s, 3H), 3.70 (d, J=8.8 Hz, 1H), 3.50(t, J=11.4 Hz, 1H), 3.43-3.32 (m, 1H), 3.22 (t, J=11.6 Hz, 1H), 2.15 (s,3H), 1.90 (d, J=12.8 Hz, 1H), 1.75 (s, 6H), 1.62-1.42 (m, 2H), 0.69 (d,J=12.5 Hz, 1H). LCMS (M+H)=526; HPLC RT=1.01 min (Column: Waters AcquityBEH C182.0×50 mm; Mobile Phase A: 10:90 ACN:water with 0.1% TFA; MobilePhase B: 90:10 ACN:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 1.5 min; Flow: 1 mL/min).

Step 7:[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-6-yl]methanol

A solution of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-(hydroxymethyl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(122 mg, 0.230 mmol) was treated with conc. aq. H₂SO₄ (100 μl, 1.88mmol) and heated to 50° C. for 60 min. The reaction was partitionedbetween ethyl acetate and sat. aq. Na₂CO₃. The organic phase was driedand evaporated under reduced pressure. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-55% B over25 min, then a 5-min hold at 55% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The yield of the product was 7.10 mg. ¹H NMR (500 MHz,DMSO-d₆) δ 8.52 (s, 1H), 8.23 (d, J=7.7 Hz, 1H), 8.17 (s, 1H), 7.63 (d,J=7.4 Hz, 2H), 7.39-7.33 (m, 2H), 7.30-7.21 (m, 2H), 5.77-5.70 (m, 1H),5.68-5.62 (m, 1H), 5.14 (d, J=11.1 Hz, 1H), 3.94-3.84 (m, 4H), 3.74 (d,J=8.8 Hz, 1H), 3.24 (t, J=11.4 Hz, 1H), 2.22 (s, 3H), 1.77 (d, J=12.5Hz, 1H), 1.58 (d, J=4.7 Hz, 6H), 1.52-1.42 (m, 2H), 1.32-1.18 (m, 2H),0.88 (d, J=12.1 Hz, 1H). LCMS (M+H)=508; HPLC RT=1.16 min (Column:Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90 ACN:water with0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA; Temperature:40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Example 3572-[3-(Dimethyl-4H-1,2,4-triazol-4-yl)-5-[(R)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl3-bromo-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described for methyl3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate,methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (1.00 g, 3.28 mmol)and phenyl(tetrahydro-2H-pyran-4-yl)methanol (1.26 g, 6.55 mmol) wereconverted to the title compound (0.902 g, 57%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.62 (d, J=1.8 Hz, 1H), 8.33-8.27 (m, 1H), 7.89 (dd, J=8.1,1.3 Hz, 1H), 7.63 (d, J=7.3 Hz, 2H), 7.40-7.33 (m, 2H), 7.31-7.22 (m,1H), 5.93 (d, J=11.2 Hz, 1H), 3.94 (s, 3H), 3.92-3.85 (m, 1H), 3.71 (dd,J=11.1, 2.5 Hz, 1H), 3.57-3.47 (m, 1H), 3.31 (s, 3H), 3.29-3.22 (m, 1H),1.78-1.70 (m, 1H), 1.69-1.54 (m, 1H), 1.31 (qd, J=12.4, 4.7 Hz, 1H),0.85 (d, J=12.1 Hz, 1H). LCMS (M+H)=479; HPLC RT=1.42 min (Column:Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90 ACN:water with0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA; Temperature:40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Step 2: Methyl3-{[(2,4-dimethoxyphenyl)methyl]amino}-5-[(S)-oxan-4-yl(phenyl)methyl-5H-pyrido[3,2-b]indole-7-carboxylate

A 25 mL screw top vial was charged with methyl3-bromo-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(800 mg, 1.67 mmol) and dioxane (15 mL). Nitrogen was then bubbledthrough the solution as 2,4-dimethoxybenzylamine (0.500 mL, 3.33 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (97.0 mg, 0.167 mmol),and cesium carbonate (1090 mg, 3.34 mmol) were added, followed byaddition of bis(dibenzylideneacetone)palladium (77.0 mg, 0.134 mmol).The vial was sealed and heated to 100° C. for 24 h. The reaction wasfiltered on Celite and the volatiles were removed under reducedpressure. The reaction mixture was purified using ISCO silica gelchromatography (80 g column, gradient from 0% to 100% EtOAc/hexanes) togive the title compound (0.394 g, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.40(br. s., 1H), 8.07 (d, J=2.2 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.74 (d,J=8.1 Hz, 1H), 7.40 (d, J=7.5 Hz, 2H), 7.33-7.15 (m, 5H), 6.79 (br. s.,2H), 6.66 (d, J=2.2 Hz, 2H), 6.49 (dd, J=8.5, 2.3 Hz, 2H), 5.66 (d,J=11.0 Hz, 2H), 4.28 (d, J=5.7 Hz, 2H), 3.68-3.59 (m, 1H), 3.35 (t,J=11.0 Hz, 1H), 3.30 (s, 3H), 3.15-3.00 (m, 1H), 2.84 (br. s., 2H), 1.58(br. s., 4H), 0.78 (d, J=12.3 Hz, 2H). LCMS (M+H)=566; HPLC RT=1.17 min(Column: Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Step 3:2-[3-(Dimethyl-4H-1,2,4-triazol-4-yl)-5-[(R)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

To a 20% solution of TFA in DCM was added methyl3-{[(2,4-dimethoxyphenyl)methyl]amino}-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(394 mg, 0.697 mmol) and the resulting solution was stirred at roomtemperature for 1 h. The reaction mixture was then partitioned betweenethyl acetate and saturated Na₂CO₃. The organic phase was dried andevaporated under reduced pressure. To the crude mixture was addedN-[1-(dimethylamino)ethylidene]-N,N-dimethyl-ethanehydrazonamide (205mg, 1.20 mmol), and it was heated to 155° C. for 16 h. The reactionmixture was purified using ISCO silica gel chromatography (24 g column,gradient from 0% to 20% MeOH/DCM). The residue obtained was dissolved inTHF (2 mL) and cooled to 0° C. Methylmagnesium bromide (3M in diethylether, 0.320 mL, 0.970 mmol) was added. The reaction mixture was warmedto room temperature and stirred at that temperature for 16 h. Thereaction mixture was then partitioned between ethyl acetate andsaturated aq. Na₂CO₃. The organic phase was dried and evaporated underreduced pressure. The crude material was purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 0-100% B over 20 min, then a 0-min hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give 12 mg (20%). ¹HNMR (500 MHz, DMSO-d₆) δ 8.57 (br. s., 1H), 8.48 (s, 1H), 8.15 (d, J=8.1Hz, 2H), 7.67 (d, J=7.7 Hz, 2H), 7.50 (d, J=8.1 Hz, 1H), 7.37-7.29 (m,2H), 7.28-7.21 (m, 1H), 5.78 (d, J=11.1 Hz, 1H), 3.90 (d, J=11.4 Hz,1H), 3.76 (d, J=9.8 Hz, 1H), 3.47 (t, J=11.1 Hz, 1H), 3.32-3.23 (m, 1H),2.90 (s, 3H), 2.74 (s, 3H), 1.66 (d, J=12.1 Hz, 2H), 1.58 (s, 6H),1.38-1.28 (m, 2H), 1.05 (d, J=12.5 Hz, 2H). LCMS (M+H)=496; HPLC RT=1.00min (Column: Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Example 364 3,3,3-TrifluoropropylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate

Step 1: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a 200 mL round-bottomed flask containing methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(1.23 g, 2.49 mmol) in THF (25 mL) was added sodium hydroxide (5M, 2.49mL, 12.5 mmol), and the reaction mixture was heated to 60° C. After 16h, 100 g of ice was added, and the volatiles were removed under reducedpressure. The pH was adjusted to pH 2 with concentrated aq. HCl andextracted with ethyl acetate (2×250 mL). The reaction mixture waspurified using ISCO silica gel chromatography (80 g column, gradientfrom 0% to 10% MeOH/DCM) to give the title compound (1.15 g, 96%). ¹HNMR (400 MHz, DMSO-d₆) δ 8.69-8.49 (m, 4H), 8.35-8.26 (m, 2H), 7.93 (d,J=7.9 Hz, 1H), 7.67 (s, 1H), 7.36-7.32 (m, 2H), 7.32-7.28 (m, 3H), 5.94(d, J=11.2 Hz, 1H), 3.94-3.82 (m, 2H), 3.79-3.66 (m, 2H), 3.29-3.09 (m,2H), 2.37-2.26 (m, 4H), 1.99 (s, 3H). LCMS (M+H)=482; HPLC RT=1.05 min(Column: Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Step 2:5-{7-Isocyanato-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazolein 0.05M solution in dioxane

To a 25 mL screw top vial containing(S)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylicacid (0.193 g, 0.400 mmol), diphenylphosphoryl azide (0.216 mL, 1.00mmol), and TEA (0.139 mL, 1.00 mmol) was added dioxane (8 mL) to give asolution. This solution was heated to 60° C. for 2 h. The solution wascooled to room temperature and used without purification.

Step 3: 3,3,3-TrifluoropropylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate

To 2 ml, of 0.05 M solution of5-{7-isocyanato-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazolein dioxane was added 3,3,3-trifluoro-1-propanol (200 μL, 2.27 mmol), andthe reaction mixture was heated to 80° C. for 16 h. The volatiles wereremoved under reduced pressure. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 20 min, then a0-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to give 7.50mg (16%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.09 (br. s., 1H), 8.48 (s, 2H),8.26 (br. s., 1H), 8.14 (d, J=8.4 Hz, 1H), 7.64 (d, J=7.4 Hz, 2H), 7.43(d, J=8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.29-7.21 (m, 1H), 5.64 (br. s.,1H), 4.41 (t, J=5.7 Hz, 2H), 4.02 (br. s., 3H), 3.90 (br. s., 1H), 3.75(d, J=10.8 Hz, 1H), 3.45 (br. s., 1H), 3.27 (t, J=11.4 Hz, 1H),2.84-2.70 (m, 3H), 2.30 (s, 3H), 1.69 (d, J=12.8 Hz, 1H), 1.50 (d, J=9.1Hz, 1H), 1.35-1.21 (m, 1H), 1.07 (d, J=12.8 Hz, 1H). LCMS (M+H)=593;HPLC RT=0.89 min (Column: Waters Acquity BEH C182.0×50 mm; Mobile PhaseA: 10:90 ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1mL/min).

Example 365 MethylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate

The title compound was prepared using a procedure analogous to thatdescribed for 3,3,3-trifluoropropylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate,using MeOH (200 μL, 4.94 mmol) to give 7.90 mg (19%). ¹H NMR (500 MHz,DMSO-d₆) δ 10.02 (br. s., 1H), 8.48 (s, 2H), 8.30 (br. s., 1H), 8.12 (d,J=8.8 Hz, 1H), 7.64 (d, J=7.4 Hz, 2H), 7.42-7.31 (m, 3H), 7.29-7.20 (m,1H), 5.64 (br. s., 1H), 4.03 (br. s., 3H), 3.91 (s, 2H), 3.76 (s, 5H),2.31 (s, 4H), 1.69 (d, J=12.5 Hz, 1H), 1.51 (d, J=8.8 Hz, 1H), 1.34-1.20(m, 1H), 1.08 (d, J=11.8 Hz, 1H). LCMS (M+H)=511; HPLC RT=0.79 min(Column: Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).

Example 366 EthylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate

The title compound was prepared using a procedure analogous to thatdescribed for 3,3,3-trifluoropropylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate,using EtOH (200 μL, 3.43 mmol) to give 8.70 mg (21%). ¹H NMR (500 MHz,DMSO-d₆) δ 9.98 (br. s., 1H), 8.48 (s, 2H), 8.29 (br. s., 1H), 8.12 (d,J=8.4 Hz, 1H), 7.64 (d, J=7.7 Hz, 2H), 7.42-7.18 (m, 4H), 5.64 (br. s.,1H), 4.23 (q, J=7.1 Hz, 2H), 4.03 (br. s., 3H), 3.95-3.86 (m, 1H), 3.76(d, J=10.4 Hz, 1H), 2.31 (s, 3H), 1.69 (d, J=12.1 Hz, 1H), 1.50 (d,J=12.1 Hz, 1H), 1.38-1.21 (m, 4H), 1.08 (d, J=11.8 Hz, 1H). LCMS(M+H)=525; HPLC RT=0.84 min (Column: Waters Acquity BEH C182.0×50 mm;Mobile Phase A: 10:90 ACN:water with 0.1% TFA; Mobile Phase B: 90:10ACN:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over1.5 min; Flow: 1 mL/min).

Example 367 Propan-2-ylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate

The title compound was prepared using a procedure analogous to thatdescribed for 3,3,3-trifluoropropylN-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]carbamate,using i-PrOH (200 μL, 2.60 mmol) to give 7.20 mg (17%). ¹H NMR (500 MHz,DMSO-d₆) δ 9.91 (br. s., 1H), 8.47 (s, 1H), 8.27 (br. s., 1H), 8.11 (d,J=8.4 Hz, 1H), 7.64 (d, J=7.4 Hz, 2H), 7.48-7.14 (m, 4H), 5.63 (br. s.,1H), 5.07-4.89 (m, 1H), 4.02 (br. s., 3H), 3.91 (s, 1H), 3.75 (d, J=7.7Hz, 1H), 3.48-3.35 (m, 2H), 3.28 (t, J=11.3 Hz, 2H), 2.31 (s, 3H), 1.68(d, J=12.1 Hz, 1H), 1.50 (d, J=11.4 Hz, 1H), 1.38-1.21 (m, 7H), 1.08 (d,J=12.8 Hz, 1H). LCMS (M+H)=539; HPLC RT=0.88 min (Column: Waters AcquityBEH C182.0×50 mm; Mobile Phase A: 10:90 ACN:water with 0.1% TFA; MobilePhase B: 90:10 ACN:water with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 1.5 min; Flow: 1 mL/min).

Example 3692-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate

To a solution of (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (0.500g, 2.53 mmol) and 2,5-dibromo-3-nitropyridine (0.712 g, 2.53 mmol) inTHF (8.42 mL) was added aq. tripotassium phosphate (2M, 2.53 ml, 5.05mmol). The reaction was degassed with bubbling nitrogen, thenPdCl₂(dppf)-CH₂Cl₂ adduct (0.124 g, 0.152 mmol) was added and thereaction was heated to 70° C. for 2 h. The reaction was cooled, dilutedwith water, and extracted 3 times with EtOAc. The combined organics wereconcentrated. The residue was purified via ISCO silica gelchromatography (40 g column; Hex/EtOAc; 0 to 100%) to give methyl4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate (0.610 g, 68%). ¹H NMR(400 MHz, CDCl₃) δ 9.01 (d, J=2.1 Hz, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.02(dd, J=8.0, 1.5 Hz, 1H), 7.84-7.73 (m, 2H), 3.97 (s, 3H); LCMS(M+H)=355.1; HPLC RT=1.15 min. Analytical HPLC Method 1.

Step 2: Methyl 3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate

A solution of methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate(0.610 g, 1.72 mmol) and DPPE (0.855 g, 2.15 mmol) in o-dichlorobenzene(5.73 mL) was heated to 170° C. After 1 h, the reaction was placed onthe rotovap and concentrated. DCM and a small amount of hexanes wereadded to the residue, the solids were filtered off, and the solids werewashed twice with DCM. The filtrate was concentrated, and the residuewas purified via ISCO silica gel column chromatography (40 g column;Hex/EtOAc; 0 to 50% gradient). The solid from filtration was combinedwith the material obtained from the column to give methyl3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate (0.380 g, 1.176mmol, 68.5%). LCMS (M+H)=323.1; HPLC RT=0.88 min. Analytical HPLC Method1.

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate

A solution of 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (0.272g, 0.706 mmol), methyl3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate (0.190 g, 0.588mmol), triethylamine (0.164 ml, 1.176 mmol), and copper(I) iodide (0.017g, 0.088 mmol) in DMF (3.92 ml) was degassed with bubbling nitrogen.Tetrakis(triphenylphosphine)palladium(0) (0.068 g, 0.059 mmol) was addedand the reaction was heated to 90° C. After, 4.5 h, triethylamine (0.164ml, 1.176 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole(0.272 g, 0.706 mmol), copper(I) iodide (0.017 g, 0.088 mmol),tetrakis(triphenylphosphine)palladium(0) (0.068 g, 0.059 mmol) andtriethylamine (0.164 ml, 1.176 mmol) were added. After an additional 3h, the reaction was cooled, diluted with water, then extracted twicewith EtOAc. The organic layers were washed with ammonium hydroxide, thenbrine, then dried over sodium sulfate and concentrated. The residue waspurified via ISCO silica gel column chromatography (via ISCO silica gelcolumn chromatography (Hex/EtOAc; 0 to 100% gradient) to give methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate(0.030 g, 30.1%). ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 8.65 (d,J=1.8 Hz, 1H), 8.09 (d, J=1.0 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.70 (dd,J=10.6, 1.0 Hz, 1H), 4.04 (s, 3H), 3.99 (s, 3H), 2.39 (s, 3H); LCMS(M+H)=340.3; HPLC RT=0.73 min. Analytical HPLC Method 1.

Step 4:(S)-2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

A suspension of (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (0.0850 g,0.442 mmol), methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate(0.0600 g, 0.177 mmol), and triphenylphosphine (0.116 g, 0.442 mmol) inDCM (1.77 ml) was cooled in a water bath, and DIAD (0.0860 mL, 0.442mmol) was added. The suspended material was dissolved upon addition. Thereaction was stirred overnight, then the volatiles were removed underreduced pressure. The residue was purified via ISCO silica gel columnchromatography (24 g column; DCM/EtOAc 0 to 100% gradient) to givepartially pure (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate.This material was dissolved in THF (1770 μL) and cooled in an ice bath.methylmagnesium bromide (3M in Et₂O, 472 μL, 1.42 mmol) was added. After1.25 h, the reaction was quenched with sat. aq. NH₄Cl and extracted withEtOAc. The organic layer was washed with brine, dried with sodiumsulfate, and concentrated. The residue was purified via ISCO silica gelcolumn chromatography (12 g column; DCM/MeOH; 0 to 10% gradient). Thismaterial was further purified via preparative HPLC with the followingconditions: Column: Luna C18, 30×100 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.1% TFA; Gradient: 10-100% B over 15 min, thena 2-min hold at 100% B; Flow: 40 mL/min to give(S)-2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(6.70 mg, 7%). ¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J=1.7 Hz, 1H), 8.26(s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.3 Hz, 2H), 7.40-7.32 (m, 2H), 7.29(d, J=7.2 Hz, 1H), 7.20 (d, J=11.7 Hz, 1H), 5.79 (d, J=11.1 Hz, 1H),3.98 (s, 4H), 3.88-3.78 (m, 1H), 3.60 (s, 1H), 3.45-3.37 (m, 1H), 2.31(s, 3H), 1.97 (d, J=12.8 Hz, 1H), 1.66 (s, 6H), 1.62 (d, J=3.3 Hz, 2H),1.43 (dd, J=13.0, 4.6 Hz, 1H), 1.08 (d, J=12.7 Hz, 1H); LCMS(M+H)=514.4; HPLC RT=0.81 min. Analytical HPLC Method 1

Example 3702-[3-(Dimethyl-1,2-oxazol-4-yl)-9-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl3-(3,5-dimethylisoxazol-4-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate

To a solution of (3,5-dimethylisoxazol-4-yl)boronic acid (0.166 g, 1.18mmol) and methyl 3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate(0.190 g, 0.588 mmol) in DMF (3.92 mL) was added tripotassium phosphate(2M aqueous, 0.882 mL, 1.76 mmol). The solution was degassed withbubbling nitrogen, then PdCl₂(dppf)-DCM adduct (0.0480 g, 0.059 mmol)was added, and the reaction was heated to 90° C. After 2 h, the reactionwas cooled and diluted with water. The reaction was extracted twice withEtOAc. The organic layers were washed with 10% LiCl solution, dried withsodium sulfate, and concentrated. The residue was purified via ISCOsilica gel column chromatography (Hex/EtOAc; 0 to 100% gradient) to givemethyl3-(3,5-dimethylisoxazol-4-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate(0.0440 g, 0.130 mmol, 22%); LCMS (M+H)=340.3; HPLC RT=0.79 min.Analytical HPLC Method 1.

Step 2: (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that for2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (0.0850 g, 0.442 mmol) andmethyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate(0.0600 g, 0.177 mmol) were converted to the title compound (3.70 mg,6%). ¹H NMR (400 MHz, CDCl₃) δ 9.28 (s, 1H), 8.62 (d, J=1.8 Hz, 1H),8.06 (d, J=1.1 Hz, 1H), 7.74-7.64 (m, 2H), 3.99 (s, 3H), 2.49 (s, 3H),2.34 (s, 3H); LCMS (M+H)=514.3; HPLC RT=0.86 min. Analytical HPLC Method1.

Examples 371 & 372[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl](imino)methyl-λ⁶-sulfanone

Step 1: 5-Bromo-2-(4-(methylthio)phenyl)-3-nitropyridine

To a solution of (4-(methylthio)phenyl)boronic acid (0.500 g, 2.98 mmol)and (4-(methylthio)phenyl)boronic acid (0.500 g, 2.98 mmol) in THF (9.92ml) was added aq. tripotassium phosphate (2M, 2.98 ml, 5.95 mmol). Thereaction was degassed with bubbling nitrogen, then PdCl₂(dppf)-DCMadduct (0.146 g, 0.179 mmol) was added, and the reaction was heated to70° C. After ca. 1.5 h, the reaction was cooled, diluted with water, andextracted 3 times with EtOAc. The organic layer was concentrated. Theresidue was purified via ISCO silica gel column chromatography (40 gcolumn; Hex/EtOAc; 0 to 50% gradient) to give5-bromo-2-(4-(methylthio)phenyl)-3-nitropyridine (0.684 g, 71%). ¹H NMR(400 MHz, CDCl₃) δ 8.89 (d, J=2.1 Hz, 1H), 8.92-8.86 (m, 1H), 8.26 (d,J=2.1 Hz, 1H), 7.51-7.45 (m, 2H), 7.36-7.29 (m, 2H), 2.53 (s, 3H).

Step 2: 3-Bromo-7-(methylthio)-5H-pyrido[3,2-b]indole

A suspension of 5-bromo-2-(4-(methylthio)phenyl)-3-nitropyridine (0.684g, 2.10 mmol) and 1,2-bis(diphenylphosphino)ethane (1.05 g, 2.63 mmol)in o-dichlorobenzene (7.01 mL) was heated to 170° C. The suspendedmaterial was dissolved as the reaction was heated. After 1.5 h, thereaction was concentrated. The residue was purified via ISCO silica gelcolumn chromatography (40 g column; Hex/EtOAc 0 to 100% gradient) togive 3-bromo-7-(methylthio)-5H-pyrido[3,2-b]indole (0.320 g, 1.09 mmol,52%). ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=2.0 Hz, 1H), 8.21 (d, J=8.3Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J=1.6 Hz, 1H),2.60 (s, 3H).

Step 3: 3-Bromo-7-(methylsulfinyl)-5H-pyrido[3,2-b]indole

To a solution of 3-bromo-7-(methylthio)-5H-pyrido[3,2-b]indole (0.220 g,0.750 mmol) in THF (12.5 mL) and water (2.50 mL) was added NBS (0.160 g,0.900 mmol). The reaction was stirred overnight, then concentrated.Water and sat. aq. NaHCO₃ solution were added, then the solid wasfiltered off and washed with water. Drying gave3-bromo-7-(methylsulfinyl)-5H-pyrido[3,2-b]indole (0.183 g, 0.592 mmol,79%). LCMS (M+H)=309.0; HPLC RT=0.87 min. Analytical HPLC Method 1.

Step 4:3-Bromo-7-(methylsulfinyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A suspension of (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (0.280 g,1.46 mmol), 3-bromo-7-(methylsulfinyl)-5H-pyrido[3,2-b]indole (0.180 g,0.582 mmol), and triphenylphosphine (0.382 g, 1.46 mmol) in DCM (5.82mL) was cooled in an ice bath. DIAD (0.283 mL, 1.46 mmol) was added; thesuspended material dissolved. The reaction was stirred overnight, thenconcentrated. The residue was purified via ISCO silica gel columnchromatography (40 g column; DCM/EtOAc 0 to 100% gradient, then DCM/MeOH0 to 10% gradient) to give3-bromo-7-(methylsulfinyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(0.333 g, 0.689 mmol, 118%) as a mixture of 2 diastereomers at thesulfoxide position. LCMS (M+H)=483.2; HPLC RT=1.07 min. Analytical HPLCMethod 1.

Step 5:3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(methylsulfinyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A solution of 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (0.319g, 0.827 mmol),3-bromo-7-(methylsulfinyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(0.333 g, 0.689 mmol) (note: weight represents greater than 100% yieldfor previous reaction), triethylamine (0.192 mL, 1.38 mmol), andcopper(I) iodide (0.0200 g, 0.103 mmol) in DMF (2.30 mL) was degassedwith bubbling nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.0520g, 0.0450 mmol) was added, and the reaction was heated to 90° C. After 2h, the reaction was cooled and then diluted with water and EtOAc. Thesolid was filtered off, then ammonium hydroxide was added, and theaqueous layer was extracted twice with EtOAc. The combined organiclayers were washed with brine, dried with sodium sulfate, andconcentrated. The residue was purified via ISCO silica gel columnchromatography (40 g column; DCM/MeOH; 0 to 10% gradient) to give3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(methylsulfinyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(0.111 g, 0.222 mmol, 32%) as a mixture of diastereomers at thesulfoxide position. LCMS (M+H)=500.4; HPLC RT=1.02 min. Analytical HPLCMethod 1.

Step 6:[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl](imino)methyl-λ⁶-sulfanone

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(methylsulfinyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(0.111 g, 0.222 mmol), 4-nitrobenzenesulfonamide (0.0900 g, 0.444 mmol),iodobenzene diacetate (0.150 g, 0.467 mmol), and ferric acetylacetonate(0.0160 g, 0.0440 mmol) were dissolved in acetonitrile (2.222 mL). Thereaction was stirred overnight, then additional4-nitrobenzenesulfonamide (0.0900 g, 0.444 mmol), ferric acetylacetonate(0.0160 g, 0.0440 mmol), and iodobenzene diacetate (0.150 g, 0.467 mmol)were added. After an additional 5 h, the reaction was concentrated. Theresidue was purified via ISCO silica gel column chromatography (40 gcolumn; DCM/MeOH; 0 to 100% gradient) to give the intermediatesulfoximine as a mixture of diastereomers. This intermediate wasdissolved in acetonitrile (2.22 mL) and Cs₂CO₃ (0.289 g, 0.888 mmol) andthiophenol (0.0870 mL, 0.844 mmol) were added. After 6 h, additionalCs₂CO₃ (0.289 g, 0.888 mmol) and thiophenol (0.0870 mL, 0.844 mmol) wereadded. The reaction was stirred overnight, then diluted withacetonitrile and filtered. The filtrate was concentrated. TheDCM-soluble portion of the residue was purified via ISCO silica gelcolumn chromatography (24 g column; DCM/MeOH; 0 to 10% gradient) to give3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(S-methylsulfonimidoyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indoleas a mixture of diastereomers, which were separated using chiral prepSFC (Column: Chiralpak IB 25×2 cm, 5 μm; Mobile Phase: 78/22 CO₂/MeOH;Flow: 50 mL/min). The faster eluting peak was assigned as Diastereomer A(13.0 mg, 11%); the slower eluting peak was assigned as Diastereomer B(11.6 mg, 10%). Diastereomer A: ¹H NMR (400 MHz, CD₃OD) δ 8.64-8.59 (m,2H), 8.57 (d, J=8.3 Hz, 1H), 8.42 (s, 1H), 7.99 (dd, J=8.3, 1.5 Hz, 1H),7.65 (d, J=7.3 Hz, 2H), 7.40-7.34 (m, 2H), 7.31-7.25 (m, 1H), 5.88 (d,J=11.0 Hz, 1H), 4.04-3.96 (m, 4H), 3.81 (d, J=9.0 Hz, 1H), 3.61 (s, 1H),3.45-3.39 (m, 2H), 3.29-3.27 (m, 3H), 2.33 (s, 3H), 1.98 (d, J=13.1 Hz,1H), 1.73-1.59 (m, 1H), 1.52-1.38 (m, 1H), 1.06 (d, J=12.7 Hz, 1H); LCMS(M+H)=515.3; HPLC RT=0.67 min. Analytical HPLC Method 1. Diastereomer B:¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.57 (d,J=8.3 Hz, 1H), 8.41 (s, 1H), 7.99 (dd, J=8.3, 1.5 Hz, 1H), 7.64 (d,J=7.3 Hz, 2H), 7.41-7.34 (m, 2H), 7.30 (d, J=7.3 Hz, 1H), 5.88 (d,J=11.1 Hz, 1H), 4.04-3.96 (m, 4H), 3.82 (dd, J=11.5, 2.9 Hz, 1H), 3.61(td, J=11.9, 2.1 Hz, 1H), 3.44-3.37 (m, 2H), 3.28 (s, 3H), 2.33 (s, 3H),1.96 (d, J=13.1 Hz, 1H), 1.73-1.60 (m, 1H), 1.55-1.41 (m, 1H), 1.07 (d,J=13.3 Hz, 1H); LCMS (M+H)=515.3; HPLC RT=0.67 min. Analytical HPLCMethod 1.

Examples 373 & 3743-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-3-hydroxypropanenitrile

Step 1:(S)-3-(3-(3,5-Dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)-3-oxopropanenitrile

To a solution of acetonitrile (0.0160 mL, 0.303 mmol) in THF (0.5 mL) at−78° C. was added nBuLi (2.5 M in hexane, 0.121 mL, 0.303 mmol). After 1h, a solution of (S)-methyl3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(0.0500 g, 0.101 mmol) in THF (0.5 mL) was added. After 2.75 h, thereaction was quenched with MeOH, then concentrated. The residue waspurified via ISCO silica gel column chromatography (12 g column;DCM/EtOAc; 0 to 100% gradient) to give(S)-3-(3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)-3-oxopropanenitrile(0.0520 g, 0.103 mmol, 102%). ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.47 (m,2H), 8.41 (s, 1H), 7.83 (dd, J=8.3, 1.3 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H),7.46 (d, J=7.3 Hz, 2H), 7.40-7.29 (m, 3H), 5.59 (d, J=10.6 Hz, 1H), 4.24(s, 2H), 4.06 (dd, J=11.7, 2.8 Hz, 1H), 3.85 (dd, J=11.7, 2.9 Hz, 1H),3.55 (td, J=11.9, 1.9 Hz, 1H), 3.36 (td, J=11.9, 2.0 Hz, 1H), 3.14 (d,J=11.0 Hz, 1H), 2.42 (s, 3H), 2.26 (s, 3H), 2.01 (br. S., 1H), 1.71-1.56(m, 1H), 1.44-1.32 (m, 1H), 1.14-1.03 (m, 1H); LCMS (M+H)=505.4; HPLCRT=0.91 min. Analytical HPLC Method 1.

Step 2:3-[3-(Dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-3-hydroxypropanenitrile

To a solution of(S)-3-(3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)-3-oxopropanenitrile(0.0510 g, 0.101 mmol) in methanol (1.01 mL) and THF (1.01 mL) was addedsodium borohydride (3.82 mg, 0.101 mmol). After 1 h, the reaction wasquenched with a small amount of 1M aq. HCl and then concentrated. Thematerial was dissolved in DCM and then washed with water. The DCM layerwas dried with sodium sulfate and concentrated. The crude material waspurified via preparative LC/MS with the following conditions: Column:Waters Xbridge C18, 19×250 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 23-63% B over25 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The diastereomers were separated using chiral prep SFC(Column: Chiracel OJ-H 25×3 cm, 5 μm; Mobile Phase: 75/25 CO₂/MeOH;Flow: 85 mL/min). The faster eluting peak was assigned as Diastereomer A(10.8 mg, 21%); the slower eluting peak was assigned as Diastereomer B(11.7 mg, 23%). Diastereomer A: ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (s,1H), 8.19 (br d, J=8.1 Hz, 1H), 8.11 (br s, 1H), 7.64 (br d, J=7.4 Hz,2H), 7.37 (br d, J=8.1 Hz, 1H), 7.32-7.26 (m, 2H), 7.24-7.16 (m, 1H),6.30 (br d, J=4.0 Hz, 1H), 5.72 (br d, J=11.1 Hz, 1H), 5.15 (br d, J=4.7Hz, 1H), 3.95-3.83 (m, 2H), 3.69 (br d, J=7.4 Hz, 1H), 3.53-3.43 (m,1H), 3.36 (br d, J=11.4 Hz, 1H), 3.26 (br t, J=11.4 Hz, 1H), 2.99 (br d,J=7.4 Hz, 2H), 2.43 (s, 3H), 2.25 (br s, 3H), 1.68 (br d, J=10.8 Hz,1H), 1.50 (br d, J=9.8 Hz, 1H), 1.29 (br d, J=7.7 Hz, 1H), 0.97 (br d,J=9.8 Hz, 1H); LCMS (M+H)=507.3; HPLC RT=1.66 min. Analytical HPLCMethod 2. Diastereomer B: ¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.19(d, J=8.1 Hz, 1H), 8.13 (br s, 1H), 7.65 (br d, J=7.4 Hz, 2H), 7.35 (brd, J=8.1 Hz, 1H), 7.31-7.26 (m, 2H), 7.25-7.18 (m, 1H), 6.26 (br d,J=4.0 Hz, 1H), 5.72 (br d, J=11.1 Hz, 1H), 5.17 (br d, J=5.0 Hz, 1H),3.87 (br d, J=9.1 Hz, 1H), 3.68-3.59 (m, 2H), 3.51-3.33 (m, 2H), 3.27(br t, J=11.8 Hz, 1H), 3.09-2.91 (m, 2H), 2.44 (s, 3H), 2.26 (br s, 3H),1.68 (br d, J=12.1 Hz, 1H), 1.51 (br d, J=11.1 Hz, 1H), 1.28 (br d,J=8.8 Hz, 1H), 0.97 (br d, J=12.8 Hz, 1H); LCMS (M+H)=507.4; HPLCRT=1.66 min. Analytical HPLC Method 1.

Example 3755-{8-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Step 1: 5-Bromo-2-(3-(methylsulfonyl)phenyl)-3-nitropyridine

Following a procedure analogous to that for methyl4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate,(3-(methylsulfonyl)phenyl)boronic acid (1.00 g, 5.00 mmol) and2,5-dibromo-3-nitropyridine (1.41 g, 5.00 mmol) were converted to thetitle compound (0.740 g, 41%). LCMS (M+H)=357.1; HPLC RT=0.82 min.Analytical HPLC Method 1.

Step 2: 3-Bromo-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole and3-bromo-8-(methylsulfonyl)-5H-pyrido[3,2-b]indole

Following a procedure analogous to that for methyl3-bromo-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate,5-bromo-2-(3-(methylsulfonyl)phenyl)-3-nitropyridine (0.740 g, 2.07mmol) was converted to 3-bromo-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(0.318 g, 47%) and 3-bromo-8-(methylsulfonyl)-5H-pyrido[3,2-b]indole(0.105 g, 16%). 3-Bromo-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole; ¹HNMR (400 MHz, CDCl₃) δ 9.63 (br s, 1H), 8.70 (d, J=1.8 Hz, 1H), 8.62 (d,J=7.7 Hz, 1H), 8.03 (dd, J=0.7, 1.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H),7.51 (t, J=7.8 Hz, 1H), 3.21 (s, 3H).3-Bromo-8-(methylsulfonyl)-5H-pyrido[3,2-b]indole; ¹H NMR (400 MHz,CDCl₃) δ 8.98 (s, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.13 (dd, J=8.6, 1.9 Hz,1H), 7.99 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 3.15 (s, 3H).

Step 3:3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-8-(methylsulfonyl)-5H-pyrido[3,2-b]indole

Following a procedure analogous to that for methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5H-pyrido[3,2-b]indole-7-carboxylate,3-bromo-8-(methylsulfonyl)-5H-pyrido[3,2-b]indole (110 mg, 0.338 mmol)was converted to the title compound (30.0 mg, 26%). LCMS (M+H)=342.1;HPLC RT=0.57 min. Analytical HPLC Method 1.

Step 4:5-{8-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following a procedure analogous to that for3-bromo-7-(methylsulfinyl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole,3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-(methylsulfonyl)-5H-pyrido[3,2-b]indole(0.0300 g, 0.0880 mmol) was converted into the title compound (18.0 mg,26%). ¹H NMR (400 MHz, CD₃OD) δ 8.98 (s, 1H), 8.61 (s, 1H), 8.40 (s,1H), 8.32-8.25 (m, 1H), 8.20 (br d, J=9.0 Hz, 1H), 7.65 (br d, J=7.8 Hz,2H), 7.39-7.33 (m, 2H), 7.30 (d, J=7.2 Hz, 1H), 5.88 (d, J=10.9 Hz, 1H),4.00 (s, 4H), 3.80 (br s, 1H), 3.65-3.56 (m, 2H), 3.43-3.38 (m, 1H),3.22 (s, 3H), 2.32 (s, 3H), 2.03-1.90 (m, 1H), 1.66 (s, 1H), 1.45 (s,1H), 1.07 (br d, J=8.6 Hz, 1H);). LCMS (M+H)=516.4; HPLC RT=0.78 min.Analytical HPLC Method 1.

Example 3765-{6-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Step 1:3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole

A solution of 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (0.449g, 1.16 mmol), 3-bromo-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole (0.315g, 0.969 mmol), copper(I) iodide (0.221 g, 1.16 mmol) and triethylamine(0.162 mL, 1.16 mmol) in DMF (9.69 mL) was degassed with bubblingnitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.112 g, 0.0970mmol) was added and the reaction was heated to 100° C. After 7.5 h,1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (0.449 g, 1.162mmol), copper(I) iodide (0.221 g, 1.16 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.112 g, 0.0970 mmol) wereadded, and the reaction was heated overnight. The reaction was cooled,then diluted with water and aq. ammonium hydroxide. The aqueous layerwas extracted twice with EtOAc. The organic layers were washed twicewith aq. 10% LiCl, dried with sodium sulfate, and concentrated. Theresidue was purified via ISCO silica gel column chromatography (40 gcolumn; DCM/MeOH; 0 to 10% gradient) to give3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(0.0890 g, 0.261 mmol, 27%). LCMS (M+H)=342.2; HPLC RT=0.63 min.Analytical HPLC Method 1.

Step 2:5-{6-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following a procedure analogous to that for(S)-2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol,(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (0.0510 g, 0.264 mmol) and3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(0.0450 g, 0.132 mmol) were converted to the title compound (15.0 mg,22%). ¹H NMR (400 MHz, CD₃OD) δ 8.75 (dd, J=7.8, 1.2 Hz, 1H), 8.56 (d,J=1.7 Hz, 1H), 8.43 (dd, J=7.9, 1.2 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H),7.66-7.56 (m, 3H), 7.41-7.33 (m, 2H), 7.32-7.26 (m, 1H), 6.97 (d, J=10.0Hz, 1H), 3.98 (br dd, J=11.3, 2.9 Hz, 1H), 3.77 (s, 3H), 3.73 (br dd,J=11.2, 3.6 Hz, 1H), 3.65-3.56 (m, 1H), 3.56 (s, 3H), 3.28-3.22 (m,12H), 2.15 (s, 4H), 2.00-1.87 (m, 1H), 1.77 (qd, J=12.5, 4.5 Hz, 1H),0.49 (br d, J=12.8 Hz, 1H); LCMS (M+H)=516.4; HPLC RT=0.82 min.Analytical HPLC Method 1.

Example 3775-{6-Methanesulfonyl-5-[(1S)-4,4,4-trifluoro-1-phenylbutyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole

Following a procedure analogous to that for(S)-2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-9-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol,(R)-4,4,4-trifluoro-1-phenylbutan-1-ol (0.0540 g, 0.264 mmol) and3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-(methylsulfonyl)-5H-pyrido[3,2-b]indole(0.0450 g, 0.132 mmol) were converted to the title compound (10.5 mg,15%). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (dd, J=7.7, 1.1 Hz, 1H), 8.61 (d,J=1.8 Hz, 1H), 8.45 (dd, J=7.9, 1.1 Hz, 1H), 7.68-7.58 (m, 2H),7.44-7.28 (m, 6H), 3.74 (s, 3H), 3.40 (s, 3H), 3.04 (s, 1H), 2.88-2.76(m, 1H), 2.68-2.54 (m, 1H), 2.11 (s, 3H), 1.67-1.47 (m, 1H);). LCMS(M+H)=528.3; HPLC RT=0.92 min. Analytical HPLC Method 1.

Example 3782-{3-[4-(²H₃)Methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: (Azidomethyl)trimethylsilane

A flask was charged with sodium azide (5.09 g, 78.0 mmol) and DMF (30mL). To this was added (chloromethyl)trimethylsilane (8.00 g, 65.2mmol). The flask was fitted with a balloon of nitrogen, placed in an 80°C. bath, and stirred at that temperature for 40 h. The reaction wasallowed to cool to room temperature. The reaction flask was fitted witha jacketed vigreaux column and short path distillation head. The productwas distilled under house vacuum to give a single fraction. Collectionwas discontinued when the head temperature began to rise and there was avisible change in the way the distillate interacted with the vigreauxcolumn (went from being uniformly coated with distillate to a moreirregular distribution on the glass of the vigreaux column). Thedistilled material weighed 7.60 g (85% pure by ¹H NMR, 76%). Thematerial was used without additional purification. ¹H NMR (400 MHz,CDCl₃) δ 2.77 (s, 2H), 0.13 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 42.1,−2.6.

Step 2: 2-Chloro-1,1-bis(²H₃)methoxyethane

A flask was charged with 2-chloroacetaldehyde (50% in water, 20.0 g, 127mmol) and D4-MeOH (10 mL). To this was added calcium chloride (16.5 g,149 mmol), which gave a significant exotherm. When the exotherm ended,the reaction was placed in a 55° C. bath and held at that temperatureovernight. In the morning, the reaction was poured into a separatoryfunnel and the layers separated. The lower, viscous aqueous layer wasextracted with 15 mL of diethyl ether, which was added to the firstorganic layer. The organics were dried over MgSO₄, filtered, fitted witha jacketed vigereaux/shortpath distillation head, and warmed in aheating mantle. The fraction that distilled between 90° C. and 110° C.was retained to give 9.25 g (56%). ¹H NMR (400 MHz, CDCl₃) δ 4.54 (t,J=5.4 Hz, 1H), 3.52 (d, J=5.3 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 103.1,53.1 (m), 43.0.

Step 3: (²H₃)Methoxyethyne

To a solution of diethylamine (15.6 mL, 149 mmol) in THF (250 mL) at 0°C. was added nBuLi (2.5 M in hexanes, 59.7 mL, 149 mmol). After stirringfor 10 min, the reaction was treated with2-chloro-1,1-bis(²H₃)methoxyethane (5.67 mL, 49.8 mmol) over a few min.After stirring for 30 min at 0° C., the volatiles were removed viaconcentration under reduced pressure, venting the rotary evaporator tonitrogen. The resulting powder was pumped under high vacuum for 15 minbefore being immersed in a −78° C. bath. To this was added 125 mL ofbrine through an addition funnel as rapidly as possible, swirling theflask to aid in complete quenching of the reaction mixture. The flaskwas fitted with a 24/40→14/20 adapter and a jacketed vigereauxcolumn/shortpath distillation apparatus. The receiving flask wasimmersed in a −78° C. bath. The boiling flask was heated with a heatingmantle. A substantial fraction formed without any change in headtemperature (Fraction 1). When the head temperature began to rise, thereceiving flask was switched (Fraction 2). The temperature rose to 38°C. and stabilized at that temperature. Collection of Fraction 2 wasdiscontinued when the head temperature began to fall. Both fractionswere analyzed by HNMR. Fraction 1: 0.898 g, ca. 94% pure. ¹H NMR (500MHz, CDCl₃) δ 1.54 (s, 1H).

Step 4: 4-(²H₃)Methoxy-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole

To a solution of (azidomethyl)trimethylsilane (85.2% pure) (2.17 g, 14.3mmol) and (²H₃)methoxyethyne (0.898 g, ca. 94% pure, 14.3 mmol) in DCM(40.8 ml) at 0° C. was added a solution of copper (II) sulfatepentahydrate (0.467 g, 1.87 mmol) in water (30.7 mL). To this was slowlyadded sodium ascorbate (1.30 g, 6.54 mmol). Upon addition of theascorbate, the reaction became very dark with precipitate, and stirringbecame difficult. The reaction was stirred at room temperature over theweekend. The resulting mixture was treated with Celite and filteredthrough a second pad of Celite, rinsing with additional DCM. Theorganics (the aqueous was removed in the Celite treatments) were driedover MgSO₄, filtered, and concentrated to give 0.750 g (28%) as a verydark oil. ¹H NMR (500 MHz, CDCl₃) δ 6.88 (s, 1H), 3.83 (s, 2H), 0.16 (s,9H). ¹³C NMR (126 MHz, CDCl₃) δ 161.3, 106.6, 56.65-55.97 (m, 1C),43.07-42.42 (m, 1C), −2.16-−2.76 (m, 1C). LCMS (M+H)=189.1.

Step 5: Methyl3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

A dry, N₂ (g) flushed, 1 dram vial was charged with tetramethylammoniumacetate (22.2 mg, 0.167 mmol), bis(triphenylphosphine)palladium(II)dichloride (5.86 mg, 8.34 μmol), and (S)-methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(40.0 mg, 0.083 mmol, see Steps 1-2 of2-[8-bromo-3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland2-[3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol).To this was added4-(²H₃)methoxy-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole (31.4 mg,0.167 mmol). The vial was again flushed with nitrogen. To this was addedNMP (0.4 mL). The resulting mixture was stirred vigorously under astream of nitrogen for 10 min. The vial was placed in a pre-heated oilbath at 95° C. and heated at that temperature overnight. The reactionwas cooled to room temperature, diluted with EtOAc, washed with water(2×), then brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by column chromatography (50% EtOAc/Hex 100% EtOAc)to give 32.0 mg (75%) as an off-white solid. ¹H NMR (500 MHz, CDCl₃) δ8.50 (s, 1H), 8.44 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz,1H), 7.71 (s, 1H), 7.22 (t, J=7.3 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.21(d, J=7.5 Hz, 1H), 7.18 (dd, J=7.5, 7.3 Hz, 1H), 7.18 (dd, J=7.5, 7.3Hz, 1H), 6.52 (d, J=5.8 Hz, 1H), 4.33 (s, 3H), 3.97 (s, 3H), 3.84 (ddd,J=11.6, 4.5, 3.5 Hz, 1H), 3.84 (ddd, J=11.6, 4.5, 3.5 Hz, 1H), 3.84(ddd, J=11.8, 11.6, 4.5 Hz, 1H), 3.84 (ddd, J=11.8, 11.6, 4.5 Hz, 1H),2.70 (tdt, J=7.5, 5.8, 3.4 Hz, 1H), 1.70 (dddd, J=4.5, 3.5, 3.4, −13.9Hz, 1H), 1.67 (dddd, J=4.5, 3.5, 3.4, −13.9 Hz, 1H), 1.60 (dddd, J=11.8,7.5, 4.5, −13.9 Hz, 1H), 1.57 (dddd, J=11.8, 7.5, 4.5, −13.9 Hz, 1H).LCMS (M+H)=515.5.

Step 6:2-{3-[4-(²H₃)Methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

To a solution of methyl3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(32.0 mg, 0.0620 mmol) in THF (2 mL) at 0° C. was addedmethylmagnesiumbromide (3M in Et₂O, 0.311 mL, 0.933 mmol). The reactionwas stirred for 30 min at that temperature. The reaction was quenched byaddition of sat. aq. NH₄Cl. The reaction was diluted with ethyl acetateand poured into water. The layers were separated. The organics wereconcentrated and purified by silica gel column chromatography (100%EtOAc) to give mostly pure product. The solid was recrystallized fromwater/EtOH (2:1). The mother liquor was removed via pipette. The solidthat came with it was collected in a syringe filter. The recrystallizedsolid was rinsed twice with additional cold water/EtOH (2:1). The rinseswere again added to the syringe filter. The solid that remained in thefilter was dissolved in EtOH and added back into the recrystallizedsolid. Concentration of the ethanol gave 27.0 mg (80%). ¹H NMR (500 MHz,CDCl₃) δ 8.59 (d, J=1.9 Hz, 1H), 8.34 (d, J=8.2 Hz, 1H), 7.95 (s, 1H),7.86 (d, J=1.9 Hz, 1H), 7.53-7.48 (m, 2H), 7.44 (dd, J=8.2, 1.4 Hz, 1H),7.39-7.34 (m, 2H), 7.33-7.30 (m, 1H), 5.56 (d, J=10.7 Hz, 1H), 4.08 (dd,J=11.7, 2.6 Hz, 1H), 4.03 (s, 3H), 3.88 (dd, J=11.5, 2.8 Hz, 1H), 3.56(td, J=11.9, 2.0 Hz, 1H), 3.37 (td, J=11.9, 2.0 Hz, 1H), 3.19-3.07 (m,1H), 2.01 (d, J=13.6 Hz, 1H), 1.75 (s, 6H), 1.69-1.61 (m, 1H), 1.48-1.35(m, 2H), 1.14 (d, J=13.2 Hz, 1H). LCMS (M+H)=515.6.

Example 3792-[3-(4-Methoxy-1-Methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 4-Methoxy-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole

The title compound was prepared following a procedure analogous to thatdescribed in the preparation of methyl3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate,starting with commercially available 2-chloro-1,1-dimethoxyethane. ¹HNMR (500 MHz, CDCl₃) δ 6.88 (s, 1H), 4.00 (s, 3H), 3.83 (s, 2H), 0.17(s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 161.3, 106.6, 57.2, 42.8,−2.05-−2.90 (m, 1C). LCMS (M+H)=186.1.

Step 2: (S)-Methyl3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in the preparation of methyl3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate,starting with 4-methoxy-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole. ¹HNMR (500 MHz, CDCl₃) δ 8.66 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.44 (d,J=8.2 Hz, 1H), 8.07 (dd, J=8.2, 1.1 Hz, 1H), 7.94 (d, J=1.7 Hz, 1H),7.51 (d, J=7.4 Hz, 2H), 7.40-7.35 (m, 2H), 7.34-7.29 (m, 1H), 5.59 (d,J=10.7 Hz, 1H), 4.16 (s, 3H), 4.11-4.06 (m, 1H), 4.05 (s, 3H), 4.04 (s,3H), 3.87 (dd, J=11.8, 2.8 Hz, 1H), 3.56 (td, J=11.9, 2.0 Hz, 1H), 3.37(td, J=11.9, 1.9 Hz, 1H), 3.21-3.10 (m, 1H), 2.01 (d, J=13.2 Hz, 1H),1.70-1.58 (m, 1H), 1.49-1.37 (m, 1H), 1.10 (d, J=12.6 Hz, 1H). LCMS(M+H)=512.5.

Step 3:2-[3-(4-Methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

To a solution of (S)-methyl3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(77.0 mg, 0.151 mmol) in THF (3 mL) at 0° C. was added methylmagnesiumbromide (3M in Et₂O, 0.753 mL, 2.26 mmol). The reaction was stirred for30 min at that temperature. The reaction was quenched by addition ofsat. aq. NH₄Cl. The reaction was diluted with ethyl acetate and pouredinto water. The layers were separated. The organics were concentratedand purified by silica gel column chromatography (100% EtOAc) to givemostly pure product. The resulting residue was dissolved in EtOH (1.5mL). To this was added water dropwise. With each drop, there was a flashof precipitate followed by dissolution. Upon addition of the final dropa large amount of solid precipitated. The resulting suspension washeated with a heat gun with vigorous stirring, but little went back intosolution. The suspension was gently agitated on a shaker for 48 h. Theresulting solid was collected by filtration in a Buchner funnel andrinsed with 2 mL of cold water/EtOH (2:1). The solid was air dried togive 50.0 mg (64%) as a fine white powder. ¹H NMR (500 MHz, CDCl₃) δ8.59 (d, J=1.7 Hz, 1H), 8.34 (d, J=8.2 Hz, 1H), 7.96 (s, 1H), 7.86 (d,J=1.7 Hz, 1H), 7.50 (d, J=7.3 Hz, 2H), 7.44 (dd, J=8.3, 1.3 Hz, 1H),7.39-7.34 (m, 2H), 7.33-7.30 (m, 1H), 5.56 (d, J=10.7 Hz, 1H), 4.16 (s,3H), 4.08 (dd, J=11.4, 2.4 Hz, 1H), 4.03 (s, 3H), 3.88 (dd, J=11.8, 2.7Hz, 1H), 3.56 (td, J=11.9, 1.9 Hz, 1H), 3.37 (td, J=11.9, 2.0 Hz, 1H),3.13 (q, J=11.2 Hz, 1H), 2.01 (d, J=12.5 Hz, 1H), 1.96 (s, 1H), 1.75 (s,6H), 1.69-1.61 (m, 1H), 1.48-1.36 (m, 1H), 1.14 (d, J=13.2 Hz, 1H). LCMS(M+H)=512.6.

Example 3802-{3-[4-(²H₃)Methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: 4-(²H₃)Methoxy-1-(²H₃)methyl-1H-1,2,3-triazole

To a solution of (²H₃)methoxyethyne (ca. 11% in THF, 0.400 g, 0.745mmol) and d3-iodomethane (0.0700 mL, 1.127 mmol) in THF (0.6 mL) at 0°C. was added a solution of sodium azide (0.0730 g, 1.12 mmol) in water(1 mL). The flask was sealed and stirred overnight at room temperature.The reaction was cooled to 0° C. and treated sequentially withcopper(II) sulfate pentahydrate (0.0240 g, 0.0980 mmol) and sodiumascorbate (0.0740 g, 0.372 mmol). The mixture was stirred vigorously for4 days. The resulting mixture was diluted with EtOAc, treated withCelite, filtered through a second pad of Celite, and concentrated. Thecrude product was purified by silica gel column chromatography(EtOAc/Hex) to give 0.0670 g (76%). ¹H NMR (500 MHz, CDCl₃) δ 6.99 (s,1H). LCMS (M+H)=120.1.

Step 2: Methyl3-[4-(²H₃)methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

A dry, N₂ (g) flushed, 1 dram vial was charged with tetramethylammoniumacetate (16.7 mg, 0.125 mmol), bis(triphenylphosphine)palladium(II)dichloride (4.39 mg, 6.26 μmol), and (S)-methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(30.0 mg, 0.0630 mmol, see Steps 1-2 of2-[8-bromo-3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland2-[3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol).To this was added 4-(²H₃)methoxy-1-(²H₃)methyl-1H-1,2,3-triazole (14.9mg, 0.125 mmol). The vial was again flushed with nitrogen. To this wasadded NMP (0.5 mL). The resulting mixture was stirred vigorously under astream of nitrogen for 10 min. The vial was placed in a pre-heated oilbath at 95° C. and heated at that temperature overnight. The reactionwas cooled to room temperature, diluted with EtOAc, washed with water(2×), then brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by column chromatography (50% EtOAc/Hex) to give31.7 mg (98%) as clear oil. LCMS (M+H)=518.5. HPLC RT=1.58 min (Column:Phenomenex LUNA C18 2×30 mm; Mobile Phase A: 10:90 ACN:water with 0.1%TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 2 min; Flow: 1 mL/min).

Step 3:2-{3-[4-(²H₃)Methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

To a solution of methyl3-[4-(²H₃)methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(31.7 mg, 0.0610 mmol) in THF (1 mL) at 0° C. was added methylmagnesiumbromide (3M in Et₂O, 0.408 mL, 1.23 mmol). The reaction was stirred for30 min at that temperature. The reaction was quenched by addition ofsat. aq. NH₄Cl. The reaction was diluted with ethyl acetate and brine.The layers were separated. The organics were concentrated and purifiedby preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 20-60% B over 20 min, then a 5-min hold at 100% B; Flow: 20mL/min). The yield of the product was 16.2 mg (51%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.52 (s, 1H), 8.40 (br. s., 1H), 8.14 (d, J=8.4 Hz, 2H), 7.65(d, J=7.7 Hz, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.39-7.30 (m, 2H), 7.29-7.22(m, 1H), 5.79 (d, J=11.4 Hz, 1H), 3.90 (d, J=8.4 Hz, 1H), 3.74 (d,J=11.4 Hz, 1H), 3.54-3.32 (m, 4H), 3.26 (t, J=11.6 Hz, 1H), 1.81-1.66(m, 1H), 1.58 (s, 7H), 1.40-1.23 (m, 1H), 0.98 (d, J=13.6 Hz, 1H). LCMS(M+H)=518.5.

Example 3812-{3-[4-Methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: 4-Methoxy-1-(²H₃)methyl-1H-1,2,3-triazole

The title compound was prepared according to the procedure of2-{3-[4-(²H₃)methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,starting with methoxyethyne (prepared by the procedure used to prepare(²H₃)methoxyethyne, starting with commercially available2-chloro-1,1-dimethoxyethane). ¹H NMR (500 MHz, CDCl₃) δ 6.99 (s, 1H),4.00 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 161.8, 106.7, 57.4 (CD₃ notobserved). LCMS (M+H)=117.1.

Step 2:2-{3-[4-Methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

The title compound was prepared according to the procedure of2-{3-[4-(²H₃)methoxy-1-(²H₃)methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,starting with 4-methoxy-1-(²H₃)methyl-1H-1,2,3-triazole. ¹H NMR (500MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.41 (br. s., 1H), 8.14 (d, J=8.1 Hz, 2H),7.66 (d, J=7.3 Hz, 2H), 7.47 (d, J=8.4 Hz, 1H), 7.38-7.30 (m, 2H),7.29-7.22 (m, 1H), 5.80 (d, J=11.0 Hz, 1H), 4.03 (s, 3H), 3.90 (d, J=8.8Hz, 1H), 3.74 (d, J=9.2 Hz, 1H), 3.55-3.33 (m, 3H), 3.26 (t, J=11.9 Hz,1H), 1.76-1.67 (m, 1H), 1.58 (s, 6H), 1.39-1.21 (m, 1H), 1.10-0.93 (m,2H). LCMS (M+H)=515.6.

Example 3822-[3-(4-Ethoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

The title compound was prepared according to the procedure of2-{3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,starting with commercially available ethoxyethyne. The title compoundwas purified by preparative HPLC with the following conditions: Column:XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. ¹H NMR (500 MHz,DMSO-d₆) δ 8.55 (s, 1H), 8.42 (br. s., 1H), 8.14 (d, J=8.1 Hz, 2H), 7.67(d, J=7.7 Hz, 2H), 7.47 (d, J=8.1 Hz, 1H), 7.38-7.30 (m, 2H), 7.29-7.21(m, 1H), 5.82 (d, J=11.0 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 4.07 (br. s.,3H), 3.96-3.86 (m, 1H), 3.74 (d, J=8.8 Hz, 1H), 3.56-3.33 (m, 2H), 3.27(t, J=11.2 Hz, 1H), 3.18 (d, J=4.8 Hz, 1H), 1.73 (d, J=12.5 Hz, 1H),1.59 (s, 7H), 1.36 (t, J=7.0 Hz, 3H), 1.34-1.25 (m, 1H), 1.00 (d, J=12.5Hz, 1H). LCMS (M+H)=526.3.

Examples 383 & 3842-[8-Bromo-3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland2-[3-(4-Bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (R)-Phenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate

To (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (0.750 g, 3.90 mmol) inDCM (26.0 mL) was added triethylamine (0.952 mL, 6.83 mmol), it wascooled to 0° C., methanesulfonyl chloride (0.380 mL, 4.88 mmol) was thenadded dropwise, and it was stirred at 0° C. for 0.5 h, then roomtemperature for 0.5 h. The reaction was cooled to 0° C. and treated with80 uL of MsCl. After 10 min, the ice bath was removed, and the reactionstirred at room temperature for 30 min. The reaction was diluted withether, washed with water, then sat. aq. NaHCO₃, then brine, dried overMgSO₄, filtered, and concentrated to give a white solid. ¹H NMR (400MHz, CDCl₃) δ 7.50-7.34 (m, 5H), 5.22 (d, J=8.8 Hz, 1H), 4.07 (dd,J=11.7, 3.1 Hz, 1H), 3.93 (dd, J=11.7, 3.1 Hz, 1H), 3.40 (td, J=11.9,2.3 Hz, 1H), 3.30 (td, J=11.8, 2.3 Hz, 1H), 2.63 (s, 3H), 2.20-2.07 (m,1H), 2.06-1.97 (m, 1H), 1.58-1.50 (m, 1H), 1.39-1.28 (m, 1H), 1.19-1.10(m, 1H).

Step 2: (S)-Methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A vial was charged with methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (600 mg, 1.97 mmol),(R)-phenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (1060 mg,3.93 mmol), cesium carbonate (1920 mg, 5.90 mmol), and DMF (5960 μL).The vial was sealed and heated at 30° C. overnight. The vial was warmedto 35° C. and held at that temperature 48 h. The vial was warmed to 45°C. and held at that temperature overnight. The reaction was cooled toroom temperature and filtered to remove undissolved solids. The solidswere rinsed with EtOAc. The organics were diluted with water/EtOAc, andthe layers separated. The organics were washed with water, then brine,dried over MgSO₄, filtered, and concentrated. The resulting residue wassuspended in 4 mL DCM. The resulting suspension was agitatedoccasionally over 5 min. The suspension was further diluted with 4 mL of25% EtOAc/Hex. The resulting suspension was filtered through a plug ofcotton and loaded on a silica gel column (150 mL SiO₂, 25% EtOAc/Hex),and eluted until the sample was adsorbed onto the column. The productwas eluted using 25% EtOAc/Hex. Fractions were visualized 1st by UV (toshow product and carboline) and then by PMA (to show benzyl alcohol(which shows blue upon charring)). Two sets of fractions were collected.The first fractions to come off were product, tainted by unreactedcarboline. These fractions were collected together and concentrated. Theresulting residue was dissolved in ether to give a fine whiteprecipitate. The precipitate (unreacted carboline) was removed byfiltration and discarded. Concentration of this mother liquor gave verypure product (502 mg, 53%). ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=1.8 Hz,1H), 8.42 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.05-7.98 (m, 2H), 7.49 (d,J=7.3 Hz, 2H), 7.41-7.34 (m, 2H), 7.31 (d, J=7.3 Hz, 1H), 5.46 (d,J=10.8 Hz, 1H), 4.07 (dd, J=11.4, 2.9 Hz, 1H), 4.03 (s, 3H), 3.86 (dd,J=11.8, 2.8 Hz, 1H), 3.57 (td, J=11.9, 1.6 Hz, 1H), 3.38 (td, J=11.9,2.0 Hz, 1H), 3.22-3.06 (m, 1H), 1.99 (d, J=13.3 Hz, 1H), 1.68-1.51 (m,1H), 1.47-1.31 (m, 1H), 1.04 (d, J=12.5 Hz, 1H). LCMS (M(⁸¹Br)+H)=481.2.

Step 3: (S)-Methyl3-(1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A dry, N₂ (g) flushed, 1 dram vial was charged with tetramethylammoniumacetate (33.3 mg, 0.250 mmol), bis(triphenylphosphine)palladiumdichloride (8.79 mg, 0.0130 mmol) and (S)-methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(60.0 mg, 0.125 mmol). To this was added 1-methyl-1H-1,2,3-triazole(20.8 mg, 0.250 mmol). The vial was again flushed with nitrogen. To thiswas added NMP (0.5 mL). The resulting mixture was stirred vigorouslyunder a stream of nitrogen for 10 min. The vial was placed in apre-heated oil bath at 95° C. and heated at that temperature overnight.The reaction was cooled to room temperature, diluted with EtOAc, washedwith water (2×), then brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by column chromatography (100%EtOAc→1% MeOH/EtOAc) to give 39.5 mg (66%) as an off-white solid. ¹H NMR(500 MHz, CDCl₃) δ 8.61 (d, J=1.6 Hz, 1H), 8.50 (s, 1H), 8.47 (d, J=8.2Hz, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.53-7.45(m, 2H), 7.42-7.35 (m, 2H), 7.35-7.30 (m, 1H), 5.63 (d, J=10.7 Hz, 1H),4.11-4.03 (m, 4H), 3.98 (s, 3H), 3.86 (dd, J=11.7, 3.0 Hz, 1H), 3.57(td, J=11.9, 1.7 Hz, 1H), 3.37 (td, J=11.9, 1.9 Hz, 1H), 3.22-3.09 (m,1H), 2.11-2.01 (m, 1H), 1.72-1.59 (m, 1H), 1.50-1.38 (m, 1H), 1.07 (d,J=13.1 Hz, 1H). LCMS (M+H)=482.3.

Step 4: (S)-Methyl3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylateand (S)-Methyl8-bromo-3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a solution of (S)-methyl3-(1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(39.5 mg, 0.0820 mmol) in DMF (0.5 mL) at room temperature was added NBS(16.1 mg, 0.0900 mmol). The reaction was placed in a preheated sand bathat 45° C. and held at that temperature for 2 h. The reaction was cooledto room temperature, diluted with DCM, and poured into water. Theorganics were washed with water (2×), then brine, dried over MgSO₄,filtered, and concentrated. Column chromatography (50%→100% EtOAc/Hex)gave two closely eluting spots which were collected together to give21.0 mg (ca. 43%) as a mixture of the title compounds. LCMS (Column:Phenomenex Luna C18 2×50 mm; Mobile Phase A: 10:90 ACN:water with 0.1%TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA; Temperature: 40° C.;Gradient: 0-100% B over 4 min; Flow: 0.8 mL/min) data:Mono-bromide:(M+H)=562.2. HPLC RT=3.14 min; Di-bromide:(M(⁷⁹Br,⁸¹Br)+H)=640.1. HPLC RT=3.37 min.

Step 5:2-[8-Bromo-3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland2-[3-(4-Bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

To a mixture of (S)-methyl3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylateand (S)-methyl8-bromo-3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(21.0 mg, 0.0350 mmol) in THF (350 μL) at 0° C. was addedmethylmagnesium bromide (3M in Et₂O, 117 μL, 0.350 mmol). The reactionwas stirred for 30 min at that temperature. The reaction was quenched byaddition of sat. aq. NH₄Cl. The reaction was diluted with ethyl acetateand poured into water. The layers were separated. The organics werewashed with water, then brine, dried over MgSO₄, filtered, andconcentrated. The resulting residue was purified by columnchromatography (50%→100% EtOAc/Hexanes→1% MeOH/EtOAc) to give twofractions. The upper spot (Fraction1) was collected, concentrated, andre-purified by preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 45-85% B over 15 min, then a 5-min hold at 100% B;Flow: 20 mL/min) to give Example 383 (6.30 mg, 28%). The lower spot(Fraction2) was collected to give Example 384 (9.40 mg, 43%). Example383: ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (s, 2H), 8.49 (br. s., 1H), 8.38(s, 1H), 7.65 (d, J=7.7 Hz, 2H), 7.40-7.32 (m, 2H), 7.30-7.24 (m, 1H),5.74 (d, J=11.0 Hz, 1H), 4.09 (s, 3H), 3.93-3.87 (m, 1H), 3.74 (d, J=8.8Hz, 1H), 3.52-3.22 (m, 3H), 1.84-1.65 (m, 8H), 1.60-1.48 (m, 1H),1.38-1.25 (m, 1H), 0.98 (d, J=12.1 Hz, 1H). LCMS (M(⁷⁹Br,⁸¹Br)+H)=640.1.Example 384: ¹H NMR (500 MHz, CDCl₃) δ 8.53 (d, J=1.7 Hz, 1H), 8.38 (d,J=8.2 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.50 (d, J=7.4 Hz,2H), 7.47 (dd, J=8.3, 1.3 Hz, 1H), 7.38-7.33 (m, 2H), 7.30 (d, J=7.3 Hz,1H), 5.59 (d, J=10.7 Hz, 1H), 4.07 (dd, J=12.1, 3.5 Hz, 1H), 4.02 (s,3H), 3.87 (dd, J=11.8, 3.0 Hz, 1H), 3.56 (td, J=11.9, 1.9 Hz, 1H), 3.37(td, J=11.9, 2.0 Hz, 1H), 3.22-3.09 (m, 1H), 2.03 (d, J=13.1 Hz, 1H),1.76 (s, 6H), 1.69-1.57 (m, 2H), 1.48-1.37 (m, 1H), 1.12 (d, J=12.5 Hz,1H). LCMS (M(⁸¹Br)+H)=562.2.

Example 3852-[3-(4-Cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

2-[3-(4-Bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(6.00 mg, 10.7 μmol), cyclopropylboronic acid (4.60 mg, 0.0540 mmol),bis(tricyclohexylphosphine)palladium dichloride (1.98 mg, 2.68 μmol),and potassium phosphate (11.4 mg, 0.0540 mmol) were placed in a vial,and the mixture was flushed with nitrogen. To this was added toluene(0.5 mL) and water (0.05 mL). The vial was flushed with nitrogen for 15min with vigorous stirring. The vial was capped and placed in apreheated 110° C. bath. The reaction was held at 110° C. for 4 h, cooledto room temperature, and concentrated under a stream of nitrogen. Theresulting residue was suspended in DCM/water and stirred vigorously. Themixture was diluted with EtOAc and the layers separated. The organicswere dried over MgSO₄, filtered, and concentrated. The residue waspurified by iterative preparative HPLC (1^(st) HPLC: Column: XBridgeC18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5-minhold at 100% B; Flow: 20 mL/min. 2^(nd) HPLC: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5-minhold at 100% B; Flow: 20 mL/min. 3^(rd) HPLC: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Gradient: 10-50% B over 30 min, then a 5-minhold at 100% B; Flow: 20 mL/min) to give 3.8 mg (55%) as a TFA salt. ¹HNMR (500 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.44 (br. s., 1H), 8.15 (d, J=8.4Hz, 2H), 7.66 (d, J=7.3 Hz, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.36-7.29 (m,2H), 7.27-7.21 (m, 1H), 5.82 (d, J=11.4 Hz, 1H), 3.98 (s, 3H), 3.93-3.86(m, 1H), 3.74 (d, J=11.0 Hz, 1H), 3.47 (t, J=12.1 Hz, 1H), 3.26 (t,J=11.7 Hz, 1H), 3.19-3.09 (m, 1H), 2.94 (br. s., 1H), 1.83 (br. s., 1H),1.72 (d, J=12.1 Hz, 1H), 1.58 (s, 6H), 1.37-1.22 (m, 2H), 1.02 (d,J=12.5 Hz, 1H), 0.96-0.77 (m, 4H). LCMS (M+H)=522.3.

Examples 386 & 3872-[8-Chloro-3-(4-chloro-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,and2-[3-(4-Chloro-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

The title compounds were prepared in an analogous manner to that used toprepare2-[8-bromo-3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland2-[3-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,replacing N-bromosuccinimide with N-chlorosuccinimide. Isolation of thetitle compounds was accomplished by preparative HPLC (Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 20-80% B over 40 min, then a5-min hold at 100% B; Flow: 20 mL/min) to give Examples 386 & 387.Example 386: ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (s, 2H), 8.48 (s, 1H),8.18 (s, 1H), 7.65 (d, J=7.7 Hz, 2H), 7.39-7.31 (m, 2H), 7.30-7.23 (m,1H), 5.74 (d, J=11.7 Hz, 1H), 4.09 (br. s., 3H), 3.94-3.87 (m, 1H), 3.74(d, J=8.8 Hz, 1H), 3.51-3.32 (m, 2H), 3.27 (t, J=11.2 Hz, 1H), 1.73 (d,J=15.0 Hz, 7H), 1.59-1.49 (m, 1H), 1.32 (d, J=8.4 Hz, 1H), 0.97 (d,J=12.1 Hz, 1H). LCMS (M+H)=550.5. Example 387: ¹H NMR (500 MHz, DMSO-d₆)δ 8.61-8.47 (m, 2H), 8.17 (d, J=8.1 Hz, 2H), 7.66 (d, J=7.3 Hz, 2H),7.49 (d, J=8.1 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.21 (m, 1H), 5.82 (d,J=11.4 Hz, 1H), 4.09 (s, 3H), 3.94-3.87 (m, 1H), 3.74 (d, J=9.2 Hz, 1H),3.52-3.22 (m, 4H), 1.70 (d, J=13.2 Hz, 1H), 1.59 (s, 7H), 1.39-1.27 (m,1H), 1.02 (d, J=11.7 Hz, 1H). LCMS (M+H)=516.4.

Example 3882-[3-(4-Ethyl-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1:4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole

To a solution of (azidomethyl)trimethylsilane (85% pure, 2.40 g, 15.7mmol) and tert-butyldimethyl(prop-2-yn-1-yloxy)silane (2.95 g, 17.3mmol) in t-butanol (40 mL) was added a solution of sodium ascorbate(3.12 g, 15.7 mmol) in water (20 mL). To this was slowly added asolution of copper (II) sulfate pentahydrate (0.785 g, 3.15 mmol) inwater (20 mL). The resulting light yellow heterogeneous mixture wasstirred vigorously overnight. The reaction was diluted with EtOAc/waterwhich gave an emulsion that was partially separable. Multiple washingswith aqueous ammonia (˜10%) gave two easily separated layers. Afterconcentration of the organics, the material was purified by columnchromatography (12%→25% EtOAc/Hex) to give 4.36 g (92%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (s, 1H), 4.85 (s, 2H), 3.91 (s,2H), 0.92 (s, 9H), 0.15 (s, 9H), 0.10 (s, 6H). ¹³C NMR (101 MHz, CDCl₃)δ 148.5, 122.1, 58.1, 42.0, 25.9, 18.3, −2.5, −5.2. LCMS (M+H)=300.2.

Step 2: (S)-Methyl3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a solution of4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole(562 mg, 1.88 mmol) in THF (6.3 mL) at −78° C. was added n-BuLi (2.5M inpentane, 801 μL, 2.00 mmol). The resulting solution was stirred at −78°C. for 1 h. The resulting yellow solution was treated with zinc chloride(290 mg, 2.13 mmol). After stirring for 30 min, the ice bath wasremoved, and the reaction stirred 1 h longer to give a clear, colorlesssolution. The resulting solution was treated with (S)-methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(600 mg, 1.25 mmol), Pd₂dba₃ (22.9 mg, 0.0250 mmol), and Ru-Phos (46.7mg, 0.100 mmol) as a mixture of solids in one portion under a constantstream of nitrogen. The resulting reddish-amber solution was sealed andimmersed in a preheated oil bath at 70° C. The reaction was allowed tostir 20 h at that temperature. The reaction was diluted with DCM, pouredinto water, and the layers separated. The organics were washed withbrine, dried over MgSO₄, filtered, and concentrated. Columnchromatography (EtOAc/Hex) gave 650 mg (74%) as a foam solid. ¹H NMR(500 MHz, CDCl₃) δ 8.62 (d, J=1.7 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J=8.2Hz, 1H), 8.08 (dd, J=8.2, 1.3 Hz, 1H), 7.97 (br. s., 1H), 7.54 (d, J=7.3Hz, 2H), 7.37-7.32 (m, 2H), 7.31-7.27 (m, 1H), 5.58 (d, J=10.9 Hz, 1H),4.80 (s, 2H), 4.05 (s, 4H), 3.85 (dd, J=11.7, 2.8 Hz, 1H), 3.66-3.51 (m,2H), 3.35 (td, J=11.9, 1.7 Hz, 1H), 3.18 (d, J=11.0 Hz, 1H), 1.99 (d,J=13.2 Hz, 1H), 1.67-1.55 (m, 1H), 1.48-1.37 (m, 1H), 1.12 (d, J=12.9Hz, 1H), 0.82 (s, 10H), 0.09 (s, 3H), 0.07 (s, 3H), 0.02 (s, 9H). LCMS(M+H)=698.4.

Step 3:(S)-2-(3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

To a solution of (S)-methyl3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(650 mg, 0.931 mmol) in THF (4660 μL) at −20° C. was addedmethylmagnesium bromide (3M in Et₂O, 32483 μL, 7.45 mmol). The resultingsolution was allowed to gradually warm to 0° C. and held at thattemperature for 15 min. The reaction was quenched by the cautiousaddition of sat. aq. NH₄Cl. The reaction was diluted with ethyl acetateand poured into water. The layers were separated. The organics werewashed with water, then brine, dried over MgSO₄, filtered, andconcentrated to give 614 mg (94%). ¹H NMR (500 MHz, CDCl₃) δ 8.53 (d,J=1.6 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.88 (br. s., 1H),7.50 (d, J=7.3 Hz, 2H), 7.45 (dd, J=8.4, 1.3 Hz, 1H), 7.34-7.23 (m, 3H),5.54 (d, J=10.9 Hz, 1H), 4.79 (s, 2H), 4.03 (dd, J=11.7, 2.7 Hz, 1H),3.84 (dd, J=11.6, 2.6 Hz, 1H), 3.65-3.50 (m, 2H), 3.32 (td, J=11.9, 1.8Hz, 1H), 3.19-3.09 (m, 1H), 1.96 (d, J=13.2 Hz, 1H), 1.75 (s, 6H),1.61-1.51 (m, 1H), 1.44-1.35 (m, 1H), 1.13 (d, J=12.8 Hz, 1H), 0.86-0.79(m, 11H), 0.07 (s, 3H), 0.05 (s, 3H), −0.01 (s, 9H). LCMS (M+H)=698.5.

Step 4:(S)-2-(3-(4-(Hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

To a solution of(S)-2-(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(614 mg, 0.880 mmol) and water (0.0320 mL, 1.76 mmol) in THF (5.6 mL) at0° C. was added tetrabutylammonium fluoride (1M in THF, 2.64 mL, 2.64mmol). After 10 min at 0° C., the ice bath was removed and stirringcontinued for 1 h. The reaction was quenched by addition of sat. aq.NH₄Cl and diluted with EtOAc. The mixture was poured into water, and thelayers separated. The organics were washed with water, then brine, driedover MgSO₄, filtered, and concentrated. Column chromatography (2%MeOH/EtOAc 10% MeOH/EtOAc) gave 376 mg (84%) as a white solid. LCMS(M+H)=512.3. HPLC RT=1.98 min (Column: Phenomenex LUNA C18, 2×50 mm;Mobile Phase A: 10:90 ACN:water with 0.1% TFA; Mobile Phase B: 90:10ACN:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4min; Flow: 0.8 mL/min).

Step 5:(S)-(5-(7-(2-Hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazol-4-yl)methylmethanesulfonate

To a solution of(S)-2-(3-(4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(125 mg, 0.244 mmol) and TEA (51.1 μL, 0.366 mmol) in DCM (1960 μL) at0° C. was added methanesulfonyl chloride (20.9 μL, 0.269 mmol) dropwise.The reaction was held at 0° C. for 30 min. The reaction was diluted withEtOAc and quenched by addition of sat. aq. NaHCO₃. After stirringbriefly at 0° C., the reaction was poured into a separatory funnel, andthe layers separated. The organics were washed with water, then brine,dried over MgSO₄, filtered, and concentrated. The resulting residue wasused without purification. LCMS (M+H)=590.1. HPLC RT=1.57 min (Column:Waters Aquity BEH C18, 2.1×50 mm; Mobile Phase A: water with 0.05% TFA;Mobile Phase B: ACN with 0.05% TFA; Temperature: 40° C.; Gradient: 2-50%B over 1.5 min; 0.5 min hold; Flow: 0.8 mL/min).

Step 6:2-[3-(4-Ethyl-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

A flask was charged with copper(I) iodide (34.9 mg, 0.183 mmol) andflushed with nitrogen. To this was added THF (0.5 mL). The resultingsuspension was vigorously stirred for 15 min, cooled to 0° C., andtreated with methylmagnesium bromide (3M in Et₂O, 0.122 mL, 0.366 mmol).After stirring at 0° C. for 15 min, the heterogeneous mixture wastreated with a solution of(S)-(5-(7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl(methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazol-4-yl)methylmethanesulfonate (18.0 mg, 0.0310 mmol) in THF (0.5 mL) dropwise. Afterstirring for 30 min, the reaction was quenched by addition of sat. aq.NH₄Cl and diluted with EtOAc. The layers were separated. The organicswere washed with 5% ammonia in water and concentrated. The resultingresidue was purified by preparative HPLC (Column: XBridge C18, 19×mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 20-60% B over 20 min, then a 5-min hold at100% B; Flow: 20 mL/min) to give 5.50 mg (35%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.52-8.32 (m, 2H), 8.16 (d, J=8.1 Hz, 2H), 7.67 (d, J=7.3 Hz,2H), 7.48 (d, J=8.4 Hz, 1H), 7.37-7.29 (m, 2H), 7.28-7.20 (m, 1H), 5.82(d, J=11.4 Hz, 1H), 3.99 (s, 3H), 3.94-3.85 (m, 1H), 3.75 (d, J=9.2 Hz,1H), 3.56-3.34 (m, 2H), 3.27 (t, J=11.4 Hz, 1H), 2.77-2.53 (m, 3H), 1.71(d, J=12.5 Hz, 1H), 1.64-1.51 (m, 7H), 1.40-1.27 (m, 1H), 1.17 (t, J=7.5Hz, 3H), 1.03 (d, J=12.5 Hz, 1H). LCMS (M+H)=510.3.

Example 3892-[3-(4-Amino-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1:(S)-5-(7-(2-Hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazole-4-carbaldehyde

To a solution of(S)-2-(3-(4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(230 mg, 0.450 mmol) in DCM (2997 μL) at room temperature was addedDess-Martin Periodinane (229 mg, 0.539 mmol). After 1 h, the reactionwas treated with a second portion of Dess-Martin Periodinane (115 mg).After 1 h, the reaction was quenched by addition of sodium thiosulfate(600 mg) in water (3 mL). After stirring at room temperature for 10 min,the mixture was diluted with EtOAc and sat. aq. NaHCO₃, and the layersseparated. The organics were washed with sat. aq. NaHCO₃, then brine,dried over MgSO₄, filtered, and concentrated to give 220 mg (96%). ¹HNMR (500 MHz, CDCl₃) δ 10.25 (s, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.37 (d,J=8.2 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 8.01 (s, 1H), 7.53 (d, J=7.3 Hz,2H), 7.46 (dd, J=8.2, 1.3 Hz, 1H), 7.38-7.32 (m, 2H), 7.32-7.26 (m, 1H),5.56 (d, J=10.9 Hz, 1H), 4.09-4.03 (m, 4H), 3.86 (dd, J=11.7, 2.8 Hz,1H), 3.58 (td, J=11.9, 1.9 Hz, 1H), 3.47 (td, J=11.9, 1.9 Hz, 1H),3.31-3.19 (m, 1H), 2.21 (s, 1H), 1.99 (d, J=13.2 Hz, 1H), 1.76 (d, J=1.3Hz, 6H), 1.64-1.55 (m, 1H), 1.46-1.36 (m, 1H), 1.11 (d, J=12.5 Hz, 1H).LCMS (M+H)=510.5.

Step 2:(S)-5-(7-(2-Hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazole-4-carboxylicacid

A stock solution of oxidant was prepared by combining sodium chlorite(96.0 mg, 1.06 mmol), sodium dihydrogenphosphate monohydrate (73.1 mg,0.530 mmol), and water (1.2 mL). Separately,(S)-5-(7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazole-4-carbaldehyde(135 mg, 0.265 mmol) was dissolved in t-BuOH (2 mL) and THF (1.3 mL),the reaction mixture cooled to 0° C., and treated with 2-methylbut-2-ene(0.312 mL, 2.65 mmol). To this was added 0.5 mL of the stock solution ofoxidant. After stirring 10 min, the rest of the stock solution was addeddropwise. After addition, the ice bath was removed, and the reactionstirred 2 h. The reaction was poured into water (3 mL) and diluted withEtOAc, which failed to solubilize the precipitate. The solid wascollected in a Buchner funnel, rinsed with water, then EtOAc, and airdried to give 63.0 mg (45%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.74-8.48 (m,2H), 8.20-8.05 (m, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.48 (d, J=8.2 Hz, 1H),7.33 (t, J=7.6 Hz, 2H), 7.27-7.21 (m, 1H), 5.77 (d, J=11.3 Hz, 1H), 3.99(br. s., 3H), 3.90 (d, J=9.3 Hz, 1H), 3.74 (d, J=8.8 Hz, 1H), 3.54-3.22(m, 5H), 1.72-1.49 (m, 8H), 1.38-1.26 (m, 1H), 1.04 (d, J=11.8 Hz, 1H).LCMS (M+H)=526.6.

Step 3:2-[3-(4-Amino-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-oland(S)-tert-butyl(5-(7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazol-4-yl)carbamate

A vial was charged with(S)-5-(7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazole-4-carboxylicacid (63.0 mg, 0.120 mmol), t-BuOH (0.75 mL), TEA (0.0250 mL, 0.180mmol), and diphenylphosphoryl azide (0.0310 mL, 0.144 mmol). The vialwas sealed. The resulting white suspension was warmed to 85° C. and heldat this temperature for 4 h. The reaction was treated with an additionalportion of TEA (0.0250 mL, 0.180 mmol) and diphenylphosphoryl azide(0.0310 mL, 0.144 mmol). The reaction was sealed and heated at 85° C.for 8 h, cooled to room temperature, and concentrated under a stream ofnitrogen. The residue was diluted with EtOAc and treated with sat. aq.NaHCO₃. The layers were separated. The organics were washed with water3× and filtered through a Buchner funnel to remove undissolved solids,which were discarded. The eluent was concentrated and purified by columnchromatography (100% EtOAc then 20% MeOH/EtOAc). The carbamate was firstto elute, followed by the free amine. The free amine was repurified bypreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient:20-60% B over 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min) togive Example 389 (13.5 mg, 22%). Example 389. ¹H NMR (500 MHz, DMSO-d₆)δ 8.52 (s, 1H), 8.35 (br. s., 1H), 8.16-8.03 (m, 2H), 7.67 (d, J=7.7 Hz,2H), 7.45 (d, J=8.4 Hz, 1H), 7.37-7.29 (m, 2H), 7.28-7.22 (m, 1H), 5.79(d, J=11.0 Hz, 1H), 4.90 (br. s., 2H), 3.99-3.86 (m, 4H), 3.74 (d, J=9.5Hz, 1H), 3.49 (t, J=11.6 Hz, 1H), 3.42 (s, 4H), 3.27 (t, J=11.6 Hz, 1H),1.72 (d, J=12.1 Hz, 1H), 1.57 (br. s., 7H), 1.32 (d, J=12.8 Hz, 1H),1.00 (d, J=13.2 Hz, 1H). LCMS (M+H)=497.0. (S)-tert-butyl(5-(7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazol-4-yl)carbamate:¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, J=1.7 Hz, 1H), 8.36 (d, J=8.2 Hz,1H), 7.98 (s, 1H), 7.91 (br. s., 1H), 7.48 (d, J=7.4 Hz, 2H), 7.45 (dd,J=8.3, 1.3 Hz, 1H), 7.36-7.31 (m, 2H), 7.29-7.25 (m, 1H), 6.46 (s, 1H),5.53 (d, J=10.7 Hz, 1H), 4.08-4.01 (m, 1H), 3.93-3.81 (m, 4H), 3.54 (td,J=11.9, 1.9 Hz, 1H), 3.38 (td, J=11.9, 1.9 Hz, 1H), 3.23-3.10 (m, 1H),1.99-1.91 (m, 1H), 1.78-1.69 (m, 9H), 1.63-1.53 (m, 1H), 1.39 (d, J=4.1Hz, 2H), 1.32 (br. s., 9H), 1.18-1.11 (m, 1H). LCMS (M+H)=597.7.

Example 3902-{3-[1-Methyl-4-(methylamino)-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

A vial was charged with (S)-tert-butyl(5-(7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)-1-methyl-1H-1,2,3-triazol-4-yl)carbamate(13.0 mg, 0.0220 mmol, see Step 3 of2-[3-(4-amino-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol)and DMF (0.75 mL). The resulting solution was cooled to 0° C. andtreated with sodium hydride (1.74 mg, 0.0440 mmol). The ice bath wasremoved and stirring continued 10 min. The reaction was re-cooled to 0°C. and treated with iodomethane (2.72 μL, 0.0440 mmol). The reaction wasstirred at 0° C. for 15 min and quenched by addition of sat. aq. NH₄Cl.The reaction was diluted with EtOAc. The mixture was washed with water(2×), then brine, dried over MgSO₄, filtered, and concentrated. Thecrude Boc-protected product was dissolved in TFA/DCM (1:5 vol/vol).After 30 min, the reaction was concentrated and purified by preparativeHPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% Bover 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min) to give 11 mg(99%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.34 (br. s., 1H),8.16-8.03 (m, 2H), 7.66 (d, J=7.7 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H),7.37-7.29 (m, 2H), 7.28-7.21 (m, 1H), 5.79 (d, J=11.0 Hz, 1H), 5.21 (d,J=5.1 Hz, 1H), 4.01-3.85 (m, 4H), 3.74 (d, J=8.4 Hz, 1H), 3.53-3.45 (m,1H), 3.26 (t, J=11.6 Hz, 1H), 2.90 (s, 1H), 2.79 (d, J=5.1 Hz, 3H), 2.74(s, 1H), 1.72 (d, J=13.2 Hz, 1H), 1.57 (s, 7H), 1.40-1.23 (m, 1H), 0.99(d, J=12.5 Hz, 1H). LCMS (M+H)=511.1.

Example 3915-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-methoxy-1-methyl-1H-1,2,3-triazole

Step 1:(S)-3-Bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A vial was charged with3-bromo-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole (200 mg, 0.615 mmol)and cesium carbonate (601 mg, 1.85 mmol). To this was added a solutionof (R)-phenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (333 mg,1.23 mmol) in DMF (3075 μL). The vial was flushed with nitrogen, sealed,and placed in a 50° C. bath. The reaction was stirred at thistemperature for 4 days. The resulting mixture was diluted with EtOAc,filtered through a plug of cotton, and purified by silica gel columnchromatography to give 215 mg (70%). ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d,J=2.0 Hz, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.28 (s, 1H), 8.09 (d, J=1.7 Hz,1H), 7.87 (dd, J=8.2, 1.3 Hz, 1H), 7.49 (d, J=7.3 Hz, 2H), 7.42-7.36 (m,2H), 7.36-7.31 (m, 1H), 5.47 (d, J=11.0 Hz, 1H), 4.08 (dd, J=11.7, 2.9Hz, 1H), 3.88 (dd, J=11.6, 3.1 Hz, 1H), 3.58 (td, J=12.0, 2.0 Hz, 1H),3.40 (td, J=11.9, 2.0 Hz, 1H), 3.17-3.11 (m, 5H), 2.00 (d, J=13.0 Hz,1H), 1.46-1.33 (m, 1H), 1.04 (d, J=12.5 Hz, 1H). LCMS (M (⁸¹Br)+H)=501.3.

Step 2:5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-methoxy-1-methyl-1H-1,2,3-triazole

A dry, N₂ (g) flushed, 1 dram vial was charged with tetramethyl ammoniumacetate (18.7 mg, 0.140 mmol), bis(triphenylphosphine)palladium(II)dichloride (4.92 mg, 7.01 μmol), and(S)-3-bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(35.0 mg, 0.0700 mmol). To this was added4-methoxy-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (26.0 mg, 0.140mmol). The vial was again flushed with nitrogen. To this was added NMP(0.4 mL). The resulting mixture was stirred vigorously under a stream ofnitrogen for 10 min. The vial was placed in a pre-heated oil bath at 95°C. and heated at that temperature overnight. The reaction was cooled toroom temperature, diluted with EtOAc, washed with water (2×), thenbrine, dried over MgSO₄, filtered, concentrated, and purified bypreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient:10-50% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min) togive 7.00 mg (18%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (br. s., 1H), 8.68(s, 1H), 8.53 (br. s., 1H), 8.48 (d, J=8.1 Hz, 1H), 7.86 (d, J=8.4 Hz,1H), 7.68 (d, J=7.7 Hz, 2H), 7.40-7.32 (m, 2H), 7.31-7.24 (m, 1H), 6.01(d, J=11.0 Hz, 1H), 4.08 (s, 3H), 4.04 (s, 3H), 3.91 (d, J=8.8 Hz, 1H),3.72 (d, J=8.8 Hz, 1H), 3.26 (t, J=11.2 Hz, 1H), 2.51 (br. s., 4H),1.79-1.57 (m, 2H), 1.42-1.18 (m, 2H), 0.92 (d, J=12.5 Hz, 1H). LCMS(M+H)=532.5.

Example 392 Propan-2-ylN-{3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}carbamate

Step 1: Phenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate

A solution of (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (450 mg, 2.34mmol) in DCM (15 mL) was treated with triethylamine (0.652 mL, 4.68mmol). The resulting solution was cooled to 0° C. and treated withmethanesulfonyl chloride (0.274 mL, 3.51 mmol) dropwise. It was stirredat 0° C. for 1 h then room temperature for 0.5 h. It was quenched withsaturated aq. sodium bicarbonate and diluted with ether. The organiclayer was washed with saturated aq. sodium bicarbonate, then brine,dried over magnesium sulfate, filtered, and concentrated to give 620 mg(quant. yield). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.36 (m, 5H), 5.23 (d,J=8.78 Hz, 1H), 4.09-3.91 (m, 2H), 3.4-3.3 (m, 2H), 2.63 (s, 3H),2.14-2.0 (m, 2H), 1.55 (m, 1H), 1.35-1.28 (m, 2H), 1.16-1.12 (m, 1H).

Step 2: (S)-Methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

To a mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate(1.20 g, 3.93 mmol) and cesium carbonate (2.56 g, 7.87 mmol) in DMF (6mL) was added phenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate(1.17 g, 4.33 mmol) in DMF (6 mL). It was stirred at room temperatureovernight. The reaction was warmed to 40° C. and held at thattemperature 24 h. To this was added an additional portion ofphenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (1.06 g, 3.94mmol) and cesium carbonate (1.28 g, 3.94 mmol). It was heated at 40° C.over the weekend. Solids were removed by filtration and discarded, andthe filtrate concentrated. Biotage purification (30% EA/Hex) gave 300 mgproduct (16%). ¹H NMR (400 MHz, CDCl₃) δ 8.6 (d, J=2.0 Hz, 1H), 8.43 (s,1H), 8.39 (d, J=8.03 Hz, 1H), 8.05-8.01 (m, 2H), 7.50 (m, 2H), 7.39-7.35(m, 2H), 7.32 (m, 1H), 5.489d, J−11.0 Hz, 1H), 4.07 (m, 1H), 4.03 (s,3H), 3.86 (m, 1H), 3.57 (m, 1H), 3.4 (m, 1H), 3.14 (m, 1H), 2.99 (m,1H), 1.6 (m, 1H), 1.4 (m, 1H), 1.06 (m, 1H); LCMS (M+H)=479.1/481.1

Step 3: Methyl3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazole-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl-5H-pyrido[3,2-b]indole-7-carboxylate

A dry, N₂ (g) flushed, 1 dram vial was charged with tetramethylammoniumacetate (38.9 mg, 0.292 mmol), bis(triphenylphosphine)palladium(II)chloride (10.3 mg, 0.0150 mmol) and (S)-methyl3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(70.0 mg, 0.146 mmol). To this was added4-(²H₃)methoxy-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole (65.5 mg,0.292 mmol). The vial was again flushed with nitrogen and NMP (1 mL) wasthen added. The resulting mixture was stirred vigorously under a streamof nitrogen for 10 min. The vial was placed in a pre-heated oil bath at95° C. and heated at that temperature overnight. The reaction was cooledto room temperature, diluted with ethyl acetate, washed with water (2×),then brine, dried over magnesium sulfate, filtered, and concentrated.Biotage purification (70% EtOAc) gave 53.0 mg (71%) as yellow oil. LCMS(M+H)=515.5, LC RT=1.613 min (Column: Phenomenex LUNA C18, 30×2, 3 u;Mobile Phase A: 90:10 water: acetonitrile with 0.1% TFA; Mobile Phase B:10:90 water:acetonitrile with 0.1% TFA; Temperature: 40° C.; Gradient:0-100% B over 2 min, hold 1 min; Flow rate: 1 mL/min).

Step 4:3-[4-(²H₃)Methoxy-1-methyl-1H-1,2,3-triazole-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl-5H-pyrido[3,2-b]indole-7-carboxylicacid

To a solution of methyl3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazole-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl-5H-pyrido[3,2-b]indole-7-carboxylate(53.0 mg, 0.103 mmol) in THF (1 mL) was added potassium hydroxide (17.3mg, 0.309 mmol). It was stirred at 50° C. overnight and concentrated.Water was added, and the resulting mixture extracted with EA (which werediscarded). The aqueous layer was then acidified to pH 5. As the pHapproached the acidic range, a white solid precipitated out. The mixturewas extracted with ethyl acetate, dried over magnesium sulfate,filtered, and concentrated to give 42.0 mg (81%). ¹H NMR (400 MHz,CDCl₃) δ 8.85 (s, 1H), 8.64 (s, 1H), 8.6 (d, J=8.0 Hz, 1H), 8.29 (d,J=8.3 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.56 (m, 2H), 7.42-7.31 (m, 3H),5.67 (d, J=10.8 Hz, 1H), 4.11 (s, 3H), 3.92 (m, 1H), 3.6 (m, 1H), 3.41(m, 1H), 3.2 (m, 1H), 2.04 (m, 2H), 1.68 (m, 1H), 1.48 (m, 1H), 1.14 (m,1H); LCMS (M+H)=501.4.

Step 5:5-{7-Isocyanato-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazole

A vial was charged with3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazole-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl-5H-pyrido[3,2-b]indole-7-carboxylicacid (42.0 mg, 0.0840 mmol), diphenylphosphoryl azide (0.0470 mL, 0.210mmol), Et₃N (0.0290 mL, 0.210 mmol), and dioxane (1.7 mL). The mixturewas heated at 60° C. for 2 h. The solution of isocyanate was used as isin the following reaction. LCMS (M+H)=498.25, LC RT=1.73 min (Column:Phenomenex LUNA C18, 30×2, 3 u; Mobile Phase A: 90:10 water:acetonitrile with 0.1% TFA; Mobile Phase B: 10:90 water: acetonitrilewith 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 2 min, hold1 min; Flow rate: 1 mL/min).

Step 6: Propan-2-ylN-{3-[4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}carbamate

Isopropanol (210 μL, 2.73 mmol) was added to5-{7-isocyanato-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-(²H₃)methoxy-1-methyl-1H-1,2,3-triazole(41.8 mg, 0.0840 mmol). It was heated at 80° C. for 3 h. It wasconcentrated and purified by prep HPLC (Column: XBridge 19×200 mm, 5 μm;Mobile Phase A: 5:95 ACN:water with 10 mm ammonium acetate; Mobile PhaseB: 95:5 ACN:water with 10 mm ammonium acetate; Gradient: 35-75% B over20 min, 5-min hold; Flow Rate: 20 mL/min) to give 33.8 mg product (72%).¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.42 (bs, 1H), 8.25 (br. s.,1H), 8.10 (d, J=8.4 Hz, 1H), 7.63 (d, J=7.7 Hz, 2H), 7.40 (d, J=8.4 Hz,1H), 7.35 (t, J=7.5 Hz, 2H), 7.29-7.23 (m, 1H), 5.6 (m, 1H), 5.06-4.91(m, 1H), 4.08 (br. s., 3H), 3.91 (d, J=8.1 Hz, 1H), 3.75 (d, J=11.0 Hz,1H), 3.34-3.23 (m, 2H), 1.69 (d, J=12.1 Hz, 1H), 1.50 (d, J=12.5 Hz,1H), 1.32 (d, J=6.2 Hz, 8H), 1.05 (d, J=12.5 Hz, 1H); LCMS (M+H)=558.5,LC RT=1.49 min.

Example 3932-{6-Chloro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)-2-chlorobenzoate

A flask was charged with 2,5-dibromo-3-nitropyridine (6.55 g, 23.24mmol) and (3-chloro-4-(methoxycarbonyl)phenyl)boronic acid (4.98 g,23.24 mmol), flushed with nitrogen, and treated with tetrahydrofuran (65mL), followed by 2M aqueous tripotassium phosphate (23.24 mL, 46.5mmol). The resulting mixture was stirred while bubbling nitrogen throughthe mixture for 30 min. To this was added PdCl₂(dppf) (0.595 g, 0.813mmol) and heated at 75° C. for 2 h. The reaction was cooled to roomtemperature and poured into a stirred mixture of water and ethylacetate. The layers were separated, the organics washed with water (2×),then brine, dried over magnesium sulfate, filtered and concentrated. Itwas purified by silica gel column chromatography (100% DCM) to give 5.76g product (67%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.97 (m, 1H),8.40 (m, 1H), 7.94 (m, 1H), 7.71 (m, 1H), 7.44 (m, 1H), 3.99 (s, 3H),LCMS (M+H)=373.2.

Step 2: Methyl 3-bromo-6-chloro-5H-pyrido[3,2-b]indole-7-carboxylate

A 250 mL flask, charged with methyl4-(5-bromo-3-nitropyridin-2-yl)-2-chlorobenzoate (5.76 g, 15.5 mmol) and1,2-bis(diphenylphosphino)ethane (6.79 g, 17.0 mmol) was flushed withnitrogen, treated with 1,2-dichlorobenzene (77 mL), and stirred under astream of nitrogen for 15 min. The flask was sealed and immersed in anoil bath at 165° C. for 3 h. The reaction was allowed to cool to roomtemperature overnight. The resulting precipitate was collected byfiltration, rinsed with a minimum of toluene, and discarded. The eluentwas concentrated and purified by Biotage (5-50% EA/Hex) to give 398 mgproduct (8%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.67 (s, 1H),8.25 (d, J=8.03 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J=8.28 Hz, 1H), 3.94 (s,3H); LCMS (M+H)=341.2.

Step 3: (S)-Methyl3-bromo-6-chloro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A dry vial, charged with methyl3-bromo-6-chloro-5H-pyrido[3,2-b]indole-7-carboxylate (160 mg, 0.471mmol), triphenylphosphine (247 mg, 0.942 mmol),(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (181 mg, 0.942 mmol), andTHF (4712 μL), was cooled to 0° C. and treated with di-tert-butylazodicarboxylate (217 mg, 0.942 mmol). The reaction was allowed togradually warm to room temperature overnight. To this was added TFA (363μL, 4.71 mmol), and the reaction mixture stirred for 10 min. Potassiumphosphate (1.5 M) was added to the reaction mixture, followed by ethylacetate. The layers were separated, and the organics concentrated.Biotage purification (25% EA/Hex) gave 246 mg product as off-white solid(57% purity by LCMS). LCMS (M+H)=515.3, LC RT=2.08 min (Column:Phenomenex LUNA C18, 30×2, 3 u; Mobile Phase A: 90:10 water:acetonitrile with 0.1% TFA; Mobile Phase B: 10:90 water: acetonitrilewith 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 2 min, hold1 min; Flow rate: 1 mL/min).

Step 4: Methyl6-chloro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

(S)-Methyl3-bromo-6-chloro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(30.0 mg, 0.0580 mmol),4-(²H₃)methyl-1-methyl-5-(tributylstanny)-1H-1,2,3-triazole (34.1 mg,0.0880 mmol), triethylamine (0.0160 mL, 0.117 mmol), and copper(I)iodide (1.11 mg, 5.84 μmol) in DMF (0.5 mL) was degassed with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (3.37 mg, 2.92 μmol) was added(turning dark), and the reaction was heated at 90° C. for 3 h. LC/MSindicates product mass. It was diluted with ethyl acetate, washed withwater (×3) and brine, dried over magnesium sulfate, filtered, andconcentrated. Biotage purification (up to 100% EA/Hex) gave 11.0 mgproduct (35%) as clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.5 (d, J=1.5 Hz,1H), 8.41 (d, J=8.03 Hz, 1H), 7.71 (d, J=8.03 Hz, 1H), 7.57-7.52 (m,3H), 7.41-7.38 (m, 2H), 7.33 (m, 1H), 4.08 (s, 3H), 3.86 (m, 1H), 3.77(s, 3H), 3.57 (m, 1H), 3.31 (m, 1H), 3.02 (m, 1H), 2.17 (m, 1H),1.75-1.6 (m, 2H), 1.35 (m, 1H), 0.72 (m, 1H); LCMS (M+H)=533.5.

Step 5:2-{6-Chloro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described in2-{5-[(1R)-2-Cyclopropyl-1-(oxan-4-yl)ethyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,methyl6-chloro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(22.0 mg, 0.0410 mmol) was converted to 5.30 mg product (24%). ¹H NMR(500 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.04 (s, 1H),7.95 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.7 Hz, 2H), 7.38-7.28 (m, 2H),7.27-7.16 (m, 2H), 5.53 (s, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.85 (s, 3H),3.75 (d, J=9.9 Hz, 1H), 3.57-3.44 (m, 2H), 3.26 (t, J=11.6 Hz, 1H), 1.92(d, J=12.5 Hz, 1H), 1.81 (d, J=11.7 Hz, 6H), 1.53-1.40 (m, 2H), 0.89 (d,J=12.1 Hz, 1H); LCMS (M+H)=533.5.

Examples 394 & 3952-{5-[(1R)-2-Cyclopropyl-1-(oxan-4-yl)ethyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (0.800g, 2.62 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (1.11g, 2.88 mmol), triethylamine (0.731 mL, 5.24 mmol), and DMF (7 mL) waspurged under a stream of nitrogen. To this was added copper(I)iodide(0.0750 g, 0.393 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.197 g, 0.170 mmol). The vial was sealed and heated at 85° C. for 1.5h, then at 95° C. for 1 h. The resulting mixture was cooled to roomtemperature, purged again with nitrogen, treated with1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (0.910 g, 2.36 mmol),copper(I)iodide (0.0750 g, 0.393 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.197 g, 0.170 mmol). The vialwas sealed and heated at 100° C. for 2 h. After cooling to roomtemperature, the reaction was diluted with water and extracted withethyl acetate. The organics were washed with water, then aqueous NH₄OH,and then brine, dried over MgSO₄, filtered, and concentrated. Theresidue was suspended in a small amount of ethyl acetate. The resultingsolid was triturated with little ethyl acetate and dried to give 325 mgproduct as pale yellow solid. The mother liquor was concentrated andpurified by silica gel column chromatography (40 g SiO₂, 100% EA to5-10% MeOH/CH₂Cl₂) to give another 175 mg product as pale yellow solid(0.500 g total, 59%). 1H NMR (400 MHz, DMSO-d6) δ 1.96 (s, 1H), 8.63 (d,J=2 Hz, 1H), 8.36 (d, J=8 Hz, 1H), 8.26 (s, 1H), 8.17 (d, J=1.76 Hz,1H), 7.91 (dd, J1=1.25 Hz, J2=8 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H),2.31 (s, 3H); LCMS (M+H)=322.1.

Step 2: 2-Cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethanol

A dry 50 mL flask was charged with magnesium (173 mg, 7.13 mmol) and acrystal of iodine. Under nitrogen, the solids were stirred vigorouslywhile being warmed with the heat gun to aerosolize the iodine. Uponcooling to room temperature, it was treated with THF (4 mL). The mixturewas warmed with a heat gun and treated with a solution of4-bromotetrahydro-2H-pyran (0.530 mL, 4.76 mmol) in THF (4 mL) dropwisevia a dry addition funnel. When addition was complete, the mixture wasplaced in a preheated oil bath, and the mixture held at reflux for 30min. After cooling to room temperature, the solution was transferred toa stirred solution of 2-cyclopropylacetaldehyde (400 mg, 2.38 mmol) inTHF (4 mL) at −78° C. After stirring for 5 min, the ice bath wasremoved, and the reaction allowed to warm to room temperature. Thereaction was placed in a 0° C. bath and quenched by the cautiousaddition of sat. aq. NH₄Cl (˜4 mL). The reaction was diluted with EtOAcand poured into brine (˜10 mL). The layers were separated, and theaqueous was extracted with a second portion of EtOAc. The resultingorganics were dried over magnesium sulfate, filtered, and concentratedto give product (410 mg, quant.) as near colorless oil, which was usedwithout purification. ¹H NMR (400 MHz, DMSO-d₆) δ 4.03-4.0 (m, 2H),3.54-3.35 (m, 3H), 1.51-1.34 (m, 4H), 0.8 (m, 1H), 0.59-0.46 (m, 2H),0.19-0.05 (m, 2H).

Step 3: Methyl5-(2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A solution of triphenylphosphine (98.0 mg, 0.373 mmol) in THF (2 mL) wascooled to −20° C. and treated with DIAD (0.0730 mL, 0.373 mmol). Afterstirring at −20° C. for 30 min, methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(60.0 mg, 0.187 mmol) was added, and stirring continued at −20° C. for30 min. To this was added a solution of2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethanol (63.6 mg, 0.373 mmol)in THF (1 mL) dropwise. The reaction was allowed to warm to roomtemperature overnight. It was concentrated and purified by silica gelcolumn chromatography (0-1% MeOH/DCM) to give 89.0 mg product (79%purity) as sticky yellow oil. LCMS (M+H)=474.2, LC RT=1.40 min (Column:Phenomenex LUNA C18, 30×2, 3 u; Mobile Phase A: 90:10 water:acetonitrilewith 0.1% TFA; Mobile Phase B: 10:90 water:acetonitrile with 0.1% TFA;Temperature: 40° C.; Gradient: 0-100% B over 2 min, hold 1 min; Flowrate: 1 mL/min).

Step 4:2-{5-[(1R)-2-Cyclopropyl-1-(oxan-4-yl)ethyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

A solution of methyl5-(2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(89.0 mg, 0.187 mmol) in THF (2 mL) was cooled to −78° C. undernitrogen. To this was added methylmagnesium bromide (3M in ether, 0.312mL, 0.935 mmol) dropwise. After 10 min, the ice bath was removed andstirring continued for 1 h. The reaction was placed in a 0° C. bath andquenched by the cautious addition of sat. aq. ammonium chloride. Thereaction was diluted with ethyl acetate and poured into brine. Thelayers were separated, and the aqueous was extracted with a secondportion of ethyl acetate. The resulting organics were dried overmagnesium sulfate, filtered, and concentrated. Prep HPLC (Column:XBridge 19×200 mm, 5 μm; Mobile Phase A: 5:95 ACN:water with 0.1% TFA;Mobile Phase B: 95:5 ACN:water with 0.1% TFA; Gradient: 10-60% B over 30min, 5-min hold; Flow Rate: 20 mL/min) gave 17.5 mg (racemic, 20%),which was further purified by chiral prep SFC (Column: ChiralCel OD-H30×250 mm, 5 μm; Mobile Phase: 85/15 CO₂/MeOH; Flow: 70 mL/min,Pressure: 150 bar, Temperature: 35° C., UV: 272 nm) to give: EnantiomerA (3.00 mg, 17%, SFC RT=14.6-16.75 min)¹H NMR (500 MHz, DMSO-d₆) δ 8.51(d, J=14.67 Hz, 1H), 8.44-8.31 (m, 1H), 8.23-8.16 (m, 1H), 7.93-7.91 (d,J=13.57 Hz, 1H), 7.47-7.43 (m, 1H), 4.66 (br. s., 1H), 4.05 (d, J=7.3Hz, 3H), 3.92 (d, J=11.4 Hz, 1H), 3.63 (m, 1H), 3.23-2.93 (m, 2H), 2.33(d, J=4.4 Hz, 3H), 1.95-1.78 (m, 1H), 1.60 (br. s., 1H), 1.56 (s, 5H),1.53 (br. s., 1H), 1.23-1.10 (m, 4H), 1.04 (br. s., 1H), 0.75 (d, J=13.6Hz, 1H), 0.16-−0.09 (m, 4H), −0.25 (d, J=14.7 Hz, 1H); LCMS (M+H)=474.2and Enantiomer B (3.70 mg, 21%, SFC RT=18.75-21.75 min) 8.51 (d, J=14.67Hz, 1H), 8.44-8.31 (m, 1H), 8.23-8.16 (m, 1H), 7.93-7.91 (d, J=13.57 Hz,1H), 7.47-7.43 (m, 1H), 4.66 (br. s., 1H), 4.05 (d, J=7.3 Hz, 3H), 3.92(d, J=11.4 Hz, 1H), 3.63 (m, 1H), 3.23-2.93 (m, 2H), 2.33 (d, J=4.4 Hz,3H), 1.95-1.78 (m, 1H), 1.60 (br. s., 1H), 1.56 (s, 5H), 1.53 (br. s.,1H), 1.23-1.10 (m, 4H), 1.04 (br. s., 1H), 0.75 (d, J=13.6 Hz, 1H),0.16-−0.09 (m, 4H), −0.25 (d, J=14.7 Hz, 1H); LCMS (M+H)=474.2.

Examples 396 & 3972-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1S)-2-methoxy-1-(oxan-4-yl)ethyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: N,2-Dimethoxy-N-methylacetamide

A solution of 2-methoxyacetic acid (1.70 mL, 22.2 mmol) indichloromethane (10 mL) was treated with oxalyl chloride (2.14 mL, 24.4mmol) at room temperature. To this was added 2 drops of DMF, and thereaction stirred overnight. This was added to a solution ofN,O-dimethylhydroxylamine hydrochloride (3.25 g, 33.3 mmol) and TEA(6.19 mL, 44.4 mmol) in dichloromethane (10 mL) at 0° C. The ice bathwas removed, and the resulting mixture stirred at room temperatureovernight. The mixture was washed with water, then 1.5M potassiumhydrogen phosphate, then 1N hydrochloric acid, then brine, andconcentrated to give 535 mg (18%). ¹H NMR (400 MHz, CDCl₃) δ 4.24 (s,2H), 3.71 (s, 3H), 3.49 (s, 3H), 3.22 (s, 3H).

Step 2: 2-Methoxy-1-(tetrahydro-2H-pyran-4-yl)ethanone

A dry 50 mL flask under nitrogen was charged with magnesium (197 mg,8.11 mmol) and a crystal of iodine. The solids were stirred vigorouslywhile being warmed with the heat gun to aerosolize the iodine. Uponcooling to room temperature, it was treated with THF (4 mL). The mixturewas warmed with a heat gun and treated with a solution of4-bromotetrahydro-2H-pyran (0.678 mL, 6.08 mmol) in THF (4 mL) dropwisevia a dry addition funnel. When addition was complete, the mixture wasplaced in a preheated oil bath, and the mixture held at reflux for 30min. After cooling to room temperature, the solution was transferred toa stirred solution of N,2-dimethoxy-N-methylacetamide (270 mg, 2.03mmol) in THF (12 mL) at −78° C. After stirring for 5 min, the ice bathwas removed and the reaction allowed to warm to room temperature. Thereaction was placed in a 0° C. bath, quenched by addition of sat. aq.ammonium chloride, concentrated, diluted with EtOAc, washed with water,then brine, dried over magnesium sulfate, filtered, and concentrated togive 260 mg (81%) as clear oil. Material was used without purification.¹H NMR (400 MHz, CDCl₃) δ 4.11 (s, 2H), 4.05-4.0 (m, 2H), 3.5-3.44 (m,2H), 3.45 (s, 3H), 2.8 (m, 1H), 1.64 (m, 2H), 1.32 (m, 2H).

Step 3: 2-Methoxy-1-(tetrahydro-2H-pyran-4-yl)ethanol

A solution of 2-methoxy-1-(tetrahydro-2H-pyran-4-yl)ethanone (60.0 mg,0.379 mmol) in methanol (1 mL) was treated with sodium borohydride (14.4mg, 0.379 mmol) in portions (effervescence) at room temperature. Afterstirring for 2 h, it was concentrated, dissolved in EA, washed with sat.aq. ammonium chloride, then brine, dried over magnesium sulfate,filtered, and concentrated to give 60.0 mg (quant.). ¹H NMR (400 MHz,CDCl₃) δ 4.07-3.96 (m, 2H), 3.59-3.47 (m, 1H), 3.46-3.31 (m, 4H),1.87-1.77 (m, 1H), 1.74-1.58 (m, 4H), 1.53-1.40 (m, 2H), 1.32 (s, 1H).

Step 4: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(2-methoxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A microwave vial was purged with nitrogen and charged with methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(60.0 mg, 0.187 mmol), 2-methoxy-1-(tetrahydro-2H-pyran-4-yl)ethanol(59.8 mg, 0.373 mmol), and degassed toluene (1.5 mL). The vial wasflushed with nitrogen, charged with cyanomethylenetrimethylphosphorane(0.747 mL, 0.373 mmol, 0.5M in THF), sealed, and heated at 110° C.overnight. It was concentrated, diluted with ethyl acetate, washed withwater, then brine, and concentrated to give 108 mg product (50% purity).¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (br. s., 1H), 8.55-8.45 (m, 2H), 8.39(br. s., 1H), 7.95 (d, J=13.2 Hz, 1H), 4.99 (br. s., 1H), 4.18 (br. s.,1H), 4.07 (s, 3H), 3.96 (s, 4H), 3.88 (br. s., 1H), 3.62 (d, J=9.5 Hz,1H), 3.33 (br. s., 1H), 3.23-2.98 (m, 4H), 2.72-2.62 (m, 1H), 2.35 (s,3H), 1.81 (br. s., 1H), 1.69 (br. s., 1H), 1.15 (br. s., 1H), 0.66 (br.s., 1H); LCMS (M+H)=464.2.

Step 5:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1S)-2-methoxy-1-(oxan-4-yl)ethyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described in2-{5-[(1R)-2-Cyclopropyl-1-(oxan-4-yl)ethyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(2-methoxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indole-7-carboxylate(108 mg, 0.233 mmol) was converted to 40.2 mg product (racemic, 37%),which was further purified by chiral prep SFC (Column: ChiralPak AS-H30×250 mm, 5 μm; Mobile Phase: 88/12 CO₂/MeOH; Flow Rate: 70 mL/min,Pressure: 150 bar, Temperature: 35° C., UV: 268 nm) to give: EnantiomerA (5.60 mg, 15%, SFC RT=8.75 min) ¹H NMR (500 MHz, DMSO-d₆) δ 8.5 (br.s., 1H), 8.36-8.3 (m, 1H), 8.21-8.16 (m, 1H), 7.96 (s, 1H), 7.45 (d,J=8.4 Hz, 1H), 4.81 (br. s., 1H), 4.29-4.13 (m, 1H), 4.05 (s, 3H),3.93-3.88 (m, 2H), 3.63 (d, J=9.2 Hz, 1H), 3.42-3.23 (m, 1H), 3.15 (s,3H), 3.05 (m, 1H), 3.63 (m, 1H), 2.33 (s, 3H), 1.87 (m, 1H), 1.63 (d,J=12.1 Hz, 1H), 1.15 (dd, J=12.1, 4.0 Hz, 1H), 0.70 (br. s., 1H); LCMS(M+H)=464.2 and Enantiomer B (6.40 mg, 17%, SFC RT=10.52 min) ¹H NMR(500 MHz, DMSO-d₆) δ 8.5 (br. s., 1H), 8.36-8.3 (m, 1H), 8.21-8.16 (m,1H), 7.96 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 4.81 (br. s., 1H), 4.29-4.13(m, 1H), 4.05 (s, 3H), 3.93-3.88 (m, 2H), 3.63 (d, J=9.2 Hz, 1H),3.42-3.23 (m, 1H), 3.15 (s, 3H), 3.05 (m, 1H), 3.63 (m, 1H), 2.33 (s,3H), 1.87 (m, 1H), 1.63 (d, J=12.1 Hz, 1H), 1.15 (dd, J=12.1, 4.0 Hz,1H), 0.70 (br. s., 1H); LCMS (M+H)=464.2.

Examples 398 & 3992-{5-[(S)-(4-Chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: (4-Chlorophenyl)(tetrahydro-2H-pyran-4-yl)methanol

Following a procedure analogous to that described in2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethanol, 4-chlorobenzaldehyde(200 mg, 1.42 mmol) was converted to 186 mg product (58%). ¹H NMR (400MHz, CDCl₃) δ 7.36-7.33 (m, 2H), 7.26 (m, 2H), 4.4 (m, 1H), 4.04 (m,1H), 3.93 (m, 1H), 3.41-3.27 (m, 2H), 1.84-1.78 (m, 1H), 1.49-1.45 (m,1H), 1.37-1.28 (m, 2H), 1.2-1.17 (m, 1H).

Step 2: Methyl5-((4-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in methyl5-(2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,(4-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (141 mg, 0.622 mmol)was converted to 115 mg product (70%). LCMS (M+H)=530.2, LC RT=1.64 min(Column: Phenomenex LUNA C18, 30×2, 3 u; Mobile Phase A: 90:10 water:acetonitrile with 0.1% TFA; Mobile Phase B: 10:90 water: acetonitrilewith 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 2 min, hold1 min; Flow rate: 1 mL/min).

Step 3:2-{5-[(S)-(4-Chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described in2-{5-[(1R)-2-Cyclopropyl-1-(oxan-4-yl)ethyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,methyl5-((4-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(115 mg, 0.217 mmol) was converted to racemic2-{5-[(S)-(4-chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by chiral prep (Column: ChiralCel OD 21×250 mm, 10μm; Mobile Phase: Solvent A 0.1% diethylamine/Heptane, Solvent Bethanol; Flow Rate: 15 mL/min; Isocratic: 20% B, 28 min; UV: 254 nm) togive: Enantiomer A (13.2 mg, 12%, SFC RT=12.4 min) ¹H NMR (500 MHz,DMSO-d₆) δ 8.51 (s, 1H), 8.38 (m, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.10 (m,1H), 7.96 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.40(d, J=8.4 Hz, 2H), 5.84 (d, J=11.4 Hz, 1H), 4.02 (br. s., 3H), 3.90 (d,J=7.7 Hz, 1H), 3.74 (d, J=8.8 Hz, 1H), 3.47 (t, J=11.4 Hz, 1H), 3.25 (t,J=11.2 Hz, 1H), 2.30 (s, 3H), 1.72-1.64 (m, 1H), 1.58 (br. s., 7H),1.37-1.13 (m, 2H), 1.01 (d, J=12.1 Hz, 1H); LCMS (M+H)=530.3, LCMS(M+H)=530.3 and Enantiomer B (13.3 mg, 12%, SFC RT=22.5 min)¹H NMR (500MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.38 (m, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.10(m, 1H), 7.96 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H),7.40 (d, J=8.4 Hz, 2H), 5.84 (d, J=11.4 Hz, 1H), 4.02 (br. s., 3H), 3.90(d, J=7.7 Hz, 1H), 3.74 (d, J=8.8 Hz, 1H), 3.47 (t, J=11.4 Hz, 1H), 3.25(t, J=11.2 Hz, 1H), 2.30 (s, 3H), 1.72-1.64 (m, 1H), 1.58 (br. s., 7H),1.37-1.13 (m, 2H), 1.01 (d, J=12.1 Hz, 1H); LCMS (M+H)=530.3, LCMS(M+H)=530.3.

Examples 400 & 4012-{5-[(S)-(3-Chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: (3-Chlorophenyl)(tetrahydro-2H-pyran-4-yl)methanol

Following a procedure analogous to that described in2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethanol, 3-chlorobenzaldehyde(200 mg, 0.162 mmol) was converted to 157 mg product (49%). ¹H NMR (400MHz, CDCl₃) δ 7.35-7.28 (m, 3H), 7.22-7.19 (m, 1H), 4.39 (d, J=7.28 Hz,1H), 4.06-4.02 (m, 2H), 3.96-3.92 (m, 2H), 3.42-3.28 (m, 2H), 1.93-1.23(m, 5H).

Step 2: Methyl5-((3-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in methyl5-(2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,(3-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (141 mg, 0.622 mmol)was converted to 120 mg product (73%). LCMS (M+H)=530.3, LC RT=1.62 min(Column: Phenomenex LUNA C18, 30×2, 3 u; Mobile Phase A: 90:10 water:acetonitrile with 0.1% TFA; Mobile Phase B: 10:90 water: acetonitrilewith 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 2 min, hold1 min; Flow rate: 1 mL/min).

Step 3:2-{5-[(S)-(3-Chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described in2-{5-[(1R)-2-Cyclopropyl-1-(oxan-4-yl)ethyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,methyl5-((3-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(120 mg, 0.226 mmol) was converted to racemic2-{5-[(S)-(3-chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-,which was separated by Chiral prep (Column: ChiralCel OD 21×250 mm, 10μm; Mobile Phase: Solvent A 0.1% diethylamine/Heptane, Solvent Bethanol; Flow Rate: 15 mL/min; Isocratic: 15% B, 60 min; UV: 254 nm) togive: Enantiomer A (3.20 mg, 3%, SFC RT=18.1 min) ¹H NMR (500 MHz,DMSO-d₆) δ 8.50-8.39 (m, 1H), 8.55-8.31 (m, 2H), 8.15 (d, J=8.1 Hz, 1H),7.79 (s, 1H), 7.62 (d, J=7.3 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.40-7.29(m, 2H), 5.85 (d, J=11.4 Hz, 1H), 4.03 (br. s., 3H), 3.90 (d, J=7.7 Hz,1H), 3.74 (d, J=11.0 Hz, 1H), 3.54-3.41 (m, 2H), 3.26 (t, J=11.4 Hz,1H), 2.31 (s, 3H), 1.70-1.51 (m, 8H), 1.31 (d, J=9.2 Hz, 1H), 1.04 (d,J=12.5 Hz, 1H); LCMS (M+H)=530.3 and Enantiomer B (3.60 mg, 3%, SFCRT=32.3 min) ¹H NMR (500 MHz, DMSO-d₆) δ 8.50-8.39 (m, 1H), 8.55-8.31(m, 2H), 8.15 (d, J=8.1 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J=7.3 Hz, 1H),7.50 (d, J=8.1 Hz, 1H), 7.40-7.29 (m, 2H), 5.85 (d, J=11.4 Hz, 1H), 4.03(br. s., 3H), 3.90 (d, J=7.7 Hz, 1H), 3.74 (d, J=11.0 Hz, 1H), 3.54-3.41(m, 2H), 3.26 (t, J=11.4 Hz, 1H), 2.31 (s, 3H), 1.70-1.51 (m, 8H), 1.31(d, J=9.2 Hz, 1H), 1.04 (d, J=12.5 Hz, 1H); LCMS (M+H)=530.3.

Examples 402 & 4032-{5-[(S)-(2-Chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Step 1: (2-Chlorophenyl)(tetrahydro-2H-pyran-4-yl)methanol

Following a procedure analogous to that described in2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethanol, 2-chlorobenzaldehyde(200 mg, 0.162 mmol) was converted to 96.0 mg product (30%). ¹H NMR (400MHz, CDCl₃) δ 7.54-7.52 (m, 1H), 7.37-7.3 (m, 2H), 7.25-7.22 (m, 1H),4.98 (m, 1H), 4.02 (m, 2H), 3.35 (m, 2H), 1.76 (m, 1H), 1.63 (m, 2H),1.32 (m, 2H).

Step 2: Methyl5-((2-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in methyl5-(2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate,(2-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (85.0 mg, 0.373 mmol)was converted to 49.0 mg product (50%). LCMS (M+H)=530.2, LC RT=1.59 min(Column: Phenomenex LUNA C18, 30×2, 3 u; Mobile Phase A: 90:10 water:acetonitrile with 0.1% TFA; Mobile Phase B: 10:90 water: acetonitrilewith 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 2 min, hold1 min; Flow rate: 1 mL/min).

Step 3:2-{5-[(S)-(2-Chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Following a procedure analogous to that described in2-{5-[(1R)-2-Cyclopropyl-1-(oxan-4-yl)ethyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,methyl5-((2-chlorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(49.0 mg, 0.0920 mmol) was converted to racemic2-{5-[(S)-(2-chlorophenyl)(oxan-4-yl)methyl]-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,which was separated by Chiral prep (Column: ChiralCel OD 21×250 mm, 10μm; Mobile Phase: Solvent A 0.1% diethylamine/Heptane, Solvent Bethanol; Flow Rate: 15 mL/min; Isocratic: 30% B, 120 min; UV: 254 nm) togive; Enantiomer A (10.2 mg, 21%, SFC RT=7.38 min) ¹H NMR (500 MHz,DMSO-d₆) δ 8.52 (s, 1H), 8.33 (d, J=7.7 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H),7.96 (s, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.42 (s,1H), 7.37 (d, J=7.3 Hz, 1H), 5.95 (d, J=11.7 Hz, 1H), 4.00 (br. s., 3H),3.93-3.83 (m, 1H), 3.71 (d, J=10.6 Hz, 1H), 3.48 (t, J=11.7 Hz, 1H),3.18 (t, J=11.6 Hz, 1H), 2.29 (m, 3H), 1.71 (br. s., 1H), 1.68-1.59 (m,1H), 1.51 (br. s., 7H), 1.42 (d, J=12.5 Hz, 1H), 0.73 (br. s., 1H); LCMS(M+H)=530.3 and Enantiomer B (10.2 mg, 21%, SFC RT=14.17 min)¹H NMR (500MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.33 (d, J=7.7 Hz, 1H), 8.13 (d, J=8.1 Hz,1H), 7.96 (s, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.42(s, 1H), 7.37 (d, J=7.3 Hz, 1H), 5.95 (d, J=11.7 Hz, 1H), 4.00 (br. s.,3H), 3.93-3.83 (m, 1H), 3.71 (d, J=10.6 Hz, 1H), 3.48 (t, J=11.7 Hz,1H), 3.18 (t, J=11.6 Hz, 1H), 2.29 (m, 3H), 1.71 (br. s., 1H), 1.68-1.59(m, 1H), 1.51 (br. s., 7H), 1.42 (d, J=12.5 Hz, 1H), 0.73 (br. s., 1H);LCMS (M+H)=530.3.

Example 405[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]methanol

A solution of methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(188 mg, 0.379 mmol) in tetrahydrofuran (4.0 mL) was cooled in an icewater bath for 5 min, then lithium aluminum hydride 2.0 M in THF (0.379mL, 0.759 mmol) was added dropwise over about 1 min. After 10 min thecooling bath was removed and stirring continued for 45 min. The mixturewas cooled again in an ice water bath and quenched with 28 μL of water,28 μL of 15% NaOH, and 84 μL of water. A small amount of sodium sulfatewas added and the mixture stirred for 20 min, filtered, and rinsed withethyl acetate. The eluent was concentrated. This material was purifiedon SiO₂ (4 g) equilibrated in 20% acetone/DCM, loaded in DCM, and elutedusing 20% acetone/DCM (200 mL), 30% acetone/DCM (200 mL) 40% acetone/DCM(200 mL). The product containing fractions were concentrated to give thetitle compound (131 mg, 73%). A sample of the purest cut from thesefractions (12.4 mg) was further purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 20-60% B over 15 min, then a 5-min hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55-8.48 (m,1H), 8.48-8.38 (m, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.11-8.03 (m, 1H), 7.96(s, 1H), 7.68 (d, J=7.3 Hz, 2H), 7.38-7.29 (m, 3H), 7.28-7.21 (m, 1H),5.79 (d, J=11.4 Hz, 1H), 4.76 (s, 2H), 4.01 (br. s., 3H), 3.93-3.86 (m,1H), 3.73 (d, J=11.4 Hz, 1H), 3.27 (t, J=11.4 Hz, 1H), 2.30 (s, 3H),1.70 (d, J=12.8 Hz, 1H), 1.56 (br. s., 1H), 1.38-1.22 (m, 1H), 1.00 (d,J=13.9 Hz, 1H). LC/MS (468, [M+H]⁺).

Example 406{[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]methyl}dimethylamine

Step 1:3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carbaldehyde

To a solution of oxalyl chloride (0.0140 mL, 0.164 mmol) in 1.0 mL ofDCM at −78° C. was added DMSO (0.0230 mL, 0.329 mmol). After 10 min, asolution of[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]methanol(64.0 mg, 0.137 mmol) in 0.5 mL of DCM was added dropwise (0.5 mLrinse). This mixture was stirred for about 10 min, then triethylamine(0.0570 mL, 0.411 mmol) was added, and the cooling bath was removed.After 2 h total reaction time, the ice bath was replaced, and thereaction quenched with water, allowed to warm to room temperature, andextracted into ethyl acetate. The combined organics were dried overMgSO₄, filtered, and concentrated. This material was purified on SiO₂ (4g) loaded on dry column in DCM and eluted using 10-30% acetone/DCM togive the title compound (59.0 mg, 93%) as a yellow film. ¹H NMR (400MHz, CDCl₃) δ 10.25 (s, 1H), 8.60-8.56 (m, 1H), 8.54 (d, J=1.8 Hz, 1H),8.31 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.51-7.44 (m, 2H),7.41-7.29 (m, 3H), 5.64 (d, J=10.5 Hz, 1H), 4.07 (dd, J=11.4, 2.9 Hz,1H), 3.90 (s, 3H), 3.88-3.83 (m, 1H), 3.56 (td, J=11.9, 1.9 Hz, 1H),3.41-3.31 (m, 1H), 3.14 (d, J=11.0 Hz, 1H), 2.32-2.28 (m, 3H), 2.05 (d,J=13.3 Hz, 1H), 1.69-1.56 (m, 1H), 1.50-1.35 (m, 1H), 1.10 (d, J=13.3Hz, 1H). LC/MS (466, [M+H]⁺).

Step 2:{[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]methyl}dimethylamine

To a solution of3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carbaldehyde(24.9 mg, 0.0530 mmol) in DCM (1.0 mL) was added dimethylamine (2.0 M inmethanol, 0.267 mL, 0.535 mmol). After 5 min, sodiumtriacetoxyborohydride (22.7 mg, 0.107 mmol) was added. The mixture wasstirred at room temperature for 1 h. An additional 10 equivalents ofdimethylamine was added followed by sodium triacetoxyborohydride (22.7mg, 0.107 mmol). After 20 h, an additional 10 equivalents ofdimethylamine was added followed by sodium triacetoxyborohydride (22.7mg, 0.107 mmol), and the resulting mixture stirred 3 h longer. Themixture was concentrated and filtered through a 0.45 μm PVDF syringefilter using methanol. The crude material was purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 20-60% B over 15 min, then a 5-min hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give the titlecompound (5.10 mg, 19%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.45(br. s., 1H), 8.18 (d, J=7.7 Hz, 1H), 8.04 (br. s., 1H), 7.67 (d, J=7.3Hz, 2H), 7.38-7.21 (m, 4H), 5.81 (d, J=11.4 Hz, 1H), 4.01 (s, 3H),3.92-3.87 (m, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.70 (br. s., 2H), 3.48 (t,J=11.4 Hz, 1H), 3.37 (br. s., 1H), 3.26 (t, J=11.2 Hz, 1H), 2.30 (s,3H), 2.25-2.18 (m, 6H), 1.69 (d, J=13.2 Hz, 1H), 1.62-1.51 (m, 1H),1.37-1.26 (m, 1H), 1.03 (d, J=12.5 Hz, 1H). LC/MS (466, [M+H]⁺).

Example 407[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl](²H₂)methanol

A solution of methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(22.7 mg, 0.0460 mmol) in THF (4.0 mL) was cooled in an ice water bathfor 5 min. To this was added lithium aluminum deuteride (2.10 mg, 0.0500mmol) as a solid in one portion. After 1 h, the mixture was quenchedwith 2 drops of water, 2 drops of 15% NaOH solution, and 3 drops ofwater. Solid sodium sulfate was added, and this mixture was diluted withethyl acetate and sonicated/filtered. The organics were further driedwith a small amount of MgSO₄, filtered, and concentrated. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% Bover 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give the title compound (8.50 mg, 39%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.52 (s, 1H), 8.44 (br. s., 1H), 8.19 (d, J=8.1 Hz, 1H), 8.08(br. s., 1H), 7.68 (d, J=7.3 Hz, 2H), 7.39-7.29 (m, 3H), 7.29-7.23 (m,1H), 5.80 (d, J=11.4 Hz, 1H), 4.01 (br. s., 3H), 3.94-3.87 (m, 1H), 3.73(d, J=8.1 Hz, 1H), 3.53-3.43 (m, 2H), 3.42 (br. s., 1H), 3.27 (t, J=11.7Hz, 1H), 2.30 (s, 3H), 1.70 (d, J=13.2 Hz, 1H), 1.61-1.48 (m, 1H), 1.31(d, J=11.7 Hz, 1H), 1.01 (d, J=12.8 Hz, 1H). LC/MS (470, [M+H]⁺).

Example 408Dicyclopropyl[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]methanol

A solution of methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(25.5 mg, 0.0510 mmol) in THF (0.5 mL) was cooled in a dry ice-acetonebath. To this was added cyclopropylmagnesium bromide (1.0 M in2-methyltetrahydrofuran, 0.515 mL, 0.515 mmol) over about 5 min. Themixture was stirred for 30 min then transferred to an ice water bath.After 2 h, the mixture was quenched with saturated aq. ammonium chloridesolution, extracted into ethyl acetate, washed with brine, dried overMgSO₄, filtered, and concentrated to give 40 mg of a yellow film. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-75% Bover 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give the title compound (5.90 mg, 21%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.51 (s, 2H), 8.15 (d, J=8.1 Hz, 2H), 7.66 (d, J=7.7 Hz, 2H),7.57 (d, J=8.1 Hz, 1H), 7.38-7.30 (m, 2H), 7.28-7.19 (m, 1H), 5.81 (d,J=11.0 Hz, 1H), 4.04 (s, 3H), 3.95-3.85 (m, 1H), 3.75 (d, J=9.5 Hz, 1H),3.48 (t, J=11.2 Hz, 1H), 3.40 (br. s., 1H), 3.27 (t, J=11.2 Hz, 1H),2.32 (s, 3H), 1.71 (d, J=12.5 Hz, 1H), 1.63-1.47 (m, 1H), 1.40-1.24 (m,3H), 1.05 (d, J=13.9 Hz, 1H), 0.64 (br. s., 2H), 0.54-0.34 (m, 4H), 0.26(dt, J=9.0, 4.3 Hz, 2H). LC/MS (548, [M+H]⁺).

Example 4092-[8-Chloro-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: Methyl8-chloro-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(26.0 mg, 0.0520 mmol) and NCS (7.36 mg, 0.0550 mmol) was dissolved inDMF (0.5 mL), and heated to 45° C. After 20 h at 45° C., the temperaturewas raised to 60° C. After 150 h, the mixture was cooled, diluted withDCM, washed with water, then brine, dried over MgSO₄, filtered, andconcentrated to give 26.8 mg of a yellow film. This material waspurified via preparative HPLC (XBridge C18 30×100 mm; A=95% water, 5%acetonitrile+10 mm ammonium acetate; B=95% acetonitrile, 5% water+10 mmammonium acetate. Method was 30% B over 30 min at 30 mL/min,wavelength=254 nm) to give the title compound as a clear/white film(11.6 mg, 39%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.8 Hz, 1H), 8.48(s, 1H), 8.22 (s, 1H), 7.62 (s, 1H), 7.46-7.41 (m, 2H), 7.39-7.31 (m,3H), 5.53 (d, J=10.5 Hz, 1H), 4.07 (s, 3H), 4.05 (s, 1H), 3.91-3.88 (m,3H), 3.86 (br. s., 1H), 3.55 (td, J=11.9, 1.8 Hz, 1H), 3.36 (td, J=11.9,2.0 Hz, 1H), 3.15-3.00 (m, J=11.0, 11.0, 11.0 Hz, 1H), 2.29 (s, 3H),2.08-2.00 (m, 1H), 1.64 (s, 1H), 1.51-1.36 (m, J=13.1, 4.3 Hz, 1H), 1.07(d, J=12.5 Hz, 1H). LC/MS (530, [M+H]⁺).

Step 2:2-[8-Chloro-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

A solution of methyl8-chloro-3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(8.50 mg, 0.0160 mmol) in THF (0.5 mL) was cooled in a dry ice/acetonebath and methylmagnesium bromide (1.0 M in THF, 0.160 mL, 0.160 mmol)was added slowly over about 5 min. After the addition was complete, themixture was stirred at this temperature for 5 min, and then the coolingbath was removed. After 30 min, the mixture was re-cooled in a dryice/acetone bath and quenched with a couple of drops of water, thenallowed to come to room temperature and concentrated. The residue waspartitioned between saturated aqueous ammonium chloride solution anddichloromethane. The aqueous portion was further extracted with 2portions of dichloromethane. The combined organics were dried overMgSO₄, filtered, and concentrated to give 8.00 mg of a clear film. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% Bover 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give the title compound (4.00 mg, 47%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.56 (s, 1H), 8.46 (br. s., 2H), 8.16 (s, 1H), 7.66 (d, J=7.7Hz, 2H), 7.40-7.31 (m, 2H), 7.30-7.24 (m, 1H), 5.74 (d, J=11.0 Hz, 1H),4.01 (s, 3H), 3.93-3.86 (m, 1H), 3.74 (d, J=10.3 Hz, 1H), 3.46 (t,J=11.0 Hz, 1H), 3.36 (d, J=4.8 Hz, 1H), 3.31-3.22 (m, 1H), 2.30 (s, 3H),1.73 (d, J=15.8 Hz, 7H), 1.60-1.47 (m, 1H), 1.31 (d, J=9.2 Hz, 1H), 0.97(d, J=11.7 Hz, 1H). LC/MS (530, [M+H]⁺).

Example 411N-{2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}methanesulfonamide

Step 1:5-[7-(2-Azidopropan-2-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

A solution of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol(195 mg, 0.393 mmol) in DCM (5.0 mL) was cooled in an ice water bath andtrimethylsilyl azide (0.131 mL, 0.984 mmol) was added. After 5 min,BF₃.OEt₂ (0.249 mL, 1.97 mmol) was added, and the mixture was stirredfor 20 min before removing the cooling bath. After 18 h, the mixture wasdiluted with water and saturated aqueous bicarbonate, extracted intoethyl acetate, washed with brine, dried over MgSO₄, filtered, andconcentrated to give the title compound (200 mg, 70%) as a yellow solid.This was consistent with desired product by 1HNMR but contained asignificant impurity (72% purity). It was carried on without additionalpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=1.8 Hz, 1H), 8.39 (d,J=8.3 Hz, 1H), 7.84 (d, J=1.0 Hz, 1H), 7.60 (s, 1H), 7.49-7.42 (m, 3H),7.39-7.29 (m, 3H), 5.57 (d, J=10.0 Hz, 1H), 4.09-4.04 (m, 1H), 3.92-3.88(m, 3H), 3.88-3.84 (m, 1H), 3.56 (td, J=12.0, 2.1 Hz, 1H), 3.36 (td,J=11.9, 1.9 Hz, 1H), 3.11 (dd, J=10.7, 3.6 Hz, 1H), 2.30 (s, 3H),2.10-1.99 (m, 1H), 1.80 (s, 3H), 1.79 (s, 3H), 1.72-1.56 (m, 1H),1.49-1.35 (m, 1H), 1.14 (d, J=13.1 Hz, 1H). LC/MS (521, [M+H]⁺).

Step 2:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine

A flask containing a solution of5-[7-(2-azidopropan-2-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole(200 mg, 0.384 mmol) in MeOH (5 mL) was vacuum purged with nitrogen.Pd/C (82.0 mg, 0.0770 mmol) was added and the flask was vacuum purgedwith H₂ (g) several times and eventually stirred at ambient temperatureunder a balloon of hydrogen. After 2 h, the mixture was vacuum purgedseveral times with nitrogen, diluted with ethyl acetate, and filteredthrough Celite to give 146 mg of a white solid. This material wassomewhat insoluble during the filtration. The crude material waspurified (12 g SiO₂) eluting with 10% acetone/DCM (150 mL), 20%acetone/DCM (200 mL), 40% acetone/DCM (100 mL), 50% acetone/DCM (100mL), 10% MeOH/DCM 100 mL. The desired product eluted in the MeOH/DCMfractions to give the title compound (56.0 mg, 30%) as a white solid. ¹HNMR (400 MHz, CD₃OD) δ 8.49 (t, J=1.9 Hz, 1H), 8.40 (dd, J=8.3, 1.3 Hz,1H), 8.30 (br. s., 1H), 8.13 (d, J=4.8 Hz, 1H), 7.66 (d, J=7.5 Hz, 2H),7.55 (dd, J=8.5, 1.3 Hz, 1H), 7.42-7.34 (m, 2H), 7.32-7.25 (m, 1H), 5.86(d, J=10.8 Hz, 1H), 4.04-3.96 (m, 4H), 3.82 (d, J=9.0 Hz, 1H), 3.62 (t,J=11.2 Hz, 1H), 3.49-3.37 (m, 1H), 2.34-2.26 (m, 3H), 2.00 (d, J=13.3Hz, 1H), 1.82 (s, 6H), 1.72-1.60 (m, 1H), 1.46 (dd, J=12.4, 4.1 Hz, 1H),1.07 (d, J=12.8 Hz, 1H), 0.93-0.80 (m, 1H). LC/MS (495, [M+H]⁺).

Step 3:N-{2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}methanesulfonamide

To a suspension of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine(17.5 mg, 0.0350 mmol) in DCM (1 mL) was added 2 drops of triethylamine(7.40 μL, 0.0530 mmol). The cloudy suspension became homogenous and wasbriefly cooled in an ice water bath and one drop ofmethanesulfonylchloride (3.03 μL, 0.0390 mmol) was added. The vial wasremoved from the bath. After 15 min, the mixture was diluted with DCM,washed with water and brine, dried over MgSO₄, filtered, andconcentrated to give a clear film (20.4 mg). The crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give the title compound (9.70 mg, 48%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.53 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 7.72 (d, J=7.3 Hz, 3H),7.50 (d, J=8.4 Hz, 1H), 7.41-7.28 (m, 2H), 7.27-7.22 (m, 1H), 5.82 (d,J=11.0 Hz, 1H), 4.03 (s, 3H), 3.95-3.88 (m, 1H), 3.73 (d, J=9.2 Hz, 1H),3.53-3.42 (m, 2H), 3.35 (d, J=5.5 Hz, 1H), 3.29 (t, J=11.4 Hz, 1H), 2.45(s, 3H), 2.32 (s, 3H), 1.79 (s, 3H), 1.76 (br. s., 3H), 1.71 (d, J=13.6Hz, 1H), 1.60-1.47 (m, 1H), 1.31 (d, J=9.5 Hz, 1H), 1.01 (d, J=12.1 Hz,1H). Two analytical LC/MS injections were used to determine the finalpurity; LC/MS (573, [M+H]⁺).

Example 412 MethylN-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}carbamate

To a suspension of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine(23.0 mg, 0.0460 mmol) in THF (1 mL) and DCM (1 mL) was added Hünig'sbase (0.0160 mL, 0.0930 mmol). The mixture was briefly cooled in an icewater bath and methyl chloroformate (4.31 μl, 0.0560 mmol) was added.After 3 h, an additional drop of chloroformate was added. After 30 min,the mixture was concentrated, taken up in methanol, and purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 40-80% B over 15 min, then a 5-minhold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to give thetitle compound (21.5 mg, 83%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (s, 1H),8.47 (br. s., 1H), 8.14 (d, J=8.4 Hz, 1H), 8.00 (br. s., 1H), 7.75 (br.s., 1H), 7.66 (d, J=7.7 Hz, 2H), 7.33 (t, J=8.1 Hz, 3H), 7.28-7.23 (m,1H), 5.79 (d, J=11.4 Hz, 1H), 4.03 (s, 3H), 3.95-3.86 (m, 2H), 3.75 (d,J=9.2 Hz, 1H), 3.57-3.41 (m, 2H), 3.36 (d, J=4.4 Hz, 1H), 3.27 (t,J=11.2 Hz, 1H), 2.31 (s, 3H), 1.68 (d, J=4.8 Hz, 7H), 1.54 (d, J=16.1Hz, 1H), 1.30 (d, J=8.4 Hz, 1H), 1.03 (d, J=12.8 Hz, 1H). LC/MS (553,[M+H]⁺).

Example 4135-[7-(3-Fluoroazetidine-1-carbonyl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

Step 1:3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylicacid

A 20 mL pressure vial was charged with methyl3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylate(200 mg, 0.404 mmol), THF (3363 μL), and water (673 μL). The resultingsolution was treated with potassium hydroxide (67.9 mg, 1.21 mmol), andthe vial sealed. After 3 h, the reaction mixture was heated to 50° C.and stirred at that temperature overnight. After 19 h, the organics wereremoved under a stream of nitrogen, and the aqueous was transferred to aseparatory funnel. The basic solution was extracted with ethyl acetate(2×), which was discarded. The aqueous was acidified to a pH of ˜4 using1 mL of 1N aq. HCl. This mixture was then adjusted to pH˜5 using a 2Msolution of aqueous tripotassium phosphate. The resulting mixture wasextracted with ethyl acetate (3×). The combined organics were dried overmagnesium sulfate and concentrated under reduced pressure to give thetitle compound (192 mg, 99%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.59 (s, 1H), 8.55 (d, J=1.5 Hz, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.17 (dd,J=8.3, 1.0 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H),7.41-7.29 (m, 4H), 5.66 (d, J=10.5 Hz, 1H), 4.13-4.05 (m, 1H), 3.92-3.86(m, 4H), 3.63-3.53 (m, 1H), 3.38 (td, J=12.0, 1.5 Hz, 1H), 3.14 (d,J=11.0 Hz, 1H), 2.32 (s, 3H), 2.10-2.02 (m, 1H), 1.74-1.61 (m, 1H),1.55-1.43 (m, 1H), 1.11 (d, J=14.3 Hz, 1H). LC/MS (481, [M+H]⁺).

Step 2:5-[7-(3-Fluoroazetidine-1-carbonyl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

A mixture of3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylicacid (10.8 mg, 0.0220 mmol), 3-fluoroazetidine hydrochloride (5.00 mg,0.0450 mmol), Hünig's base (7.83 μL, 0.0450 mmol), and HATU (12.8 mg,0.0340 mmol) in DMF (0.5 mL) was stirred at room temperature. After 1.5h, the mixture was filtered through a 0.45 μm PVDF syringe filter andpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give the title compound (7.10 mg, 56%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.60 (s, 1H), 8.49 (br. s., 1H), 8.31 (d, J=8.1 Hz, 1H), 7.68(d, J=7.7 Hz, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.40-7.29 (m, 2H), 7.29-7.22(m, 1H), 5.96 (d, J=11.0 Hz, 1H), 5.56 (br. s., 1H), 5.45 (br. s., 1H),4.52 (br. s., 3H), 4.17 (br. s., 1H), 4.01 (br. s., 3H), 3.94-3.88 (m,1H), 3.72 (d, J=9.5 Hz, 1H), 3.56-3.34 (m, 3H), 3.31-3.19 (m, 1H), 2.30(br. s., 3H), 1.79-1.68 (m, 1H), 1.61 (d, J=11.0 Hz, 1H), 1.31 (br. s.,1H), 0.95 (br. s., 1H). LC/MS (539, [M+H]⁺).

Example 4145-[7-(3,3-Difluoroazetidine-1-carbonyl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

A mixture of3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxylicacid (10.0 mg, 0.0210 mmol), 3,3-difluoroazetidine hydrochloride (5.38mg, 0.0420 mmol), Hünig's base (7.25 μL, 0.0420 mmol), and HATU (11.8mg, 0.0310 mmol) in DMF was stirred at room temperature for 1.5 h. Themixture was filtered through a 0.45 μm PVDF syringe filter and purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-65% B over 15 min, then a5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to give thetitle compound (6.40 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (s, 1H),8.48 (br. s., 1H), 8.33 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.7 Hz, 2H), 7.64(d, J=8.1 Hz, 1H), 7.39-7.30 (m, 2H), 7.30-7.18 (m, 1H), 5.97 (d, J=11.4Hz, 1H), 4.90 (br. s., 1H), 4.58 (br. s., 1H), 4.01 (br. s., 1H), 3.90(d, J=6.6 Hz, 1H), 3.73 (d, J=8.8 Hz, 1H), 3.49 (t, J=11.4 Hz, 1H),3.40-3.32 (m, 4H), 3.25 (t, J=11.7 Hz, 1H), 2.30 (br. s., 3H), 1.73 (d,J=13.2 Hz, 1H), 1.62 (d, J=10.3 Hz, 1H), 1.33 (d, J=10.3 Hz, 1H), 0.95(d, J=12.1 Hz, 1H). LC/MS (557, [M+H]⁺).

Examples 415 & 4161-Cyclopropyl-1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol

1-Cyclopropyl-1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-olwas prepared as a mixture of diastereomers according to the proceduresdescribed for1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol.Separation of the diastereomer mixture generated in the last step wasperformed using chiral preparative SFC to give Diastereomer A andDiastereomer B: Chiralpak OJ-H preparative column, 30×250 mm, 5 μm;Mobile Phase: 10% MeOH in CO₂, 150 bar; Temp: 35° C.; Flow rate: 70.0mL/min. for 47 min. UV monitored at 270 nm. Injection: 0.75 mL of ˜6mg/mL solution in MeOH (˜19 mg purified by stacked injection).Diastereomer A: ¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.43 (br. s.,1H), 8.15 (d, J=8.4 Hz, 1H), 8.11 (br. s., 1H), 7.66 (d, J=7.7 Hz, 2H),7.50 (d, J=8.1 Hz, 1H), 7.33 (t, J=7.3 Hz, 2H), 7.28-7.18 (m, 1H), 5.80(d, J=11.0 Hz, 1H), 4.01 (s, 3H), 3.89 (d, J=8.8 Hz, 1H), 3.74 (d,J=10.3 Hz, 1H), 3.49 (s, 1H), 3.41 (br. s., 1H), 3.26 (t, J=11.6 Hz,1H), 1.75-1.66 (m, 1H), 1.57 (br. s., 3H), 1.51 (br. s., 1H), 1.29 (br.s., 2H), 1.02 (d, J=12.8 Hz, 1H), 0.52 (br. s., 1H), 0.41 (d, J=6.2 Hz,2H), 0.26 (d, J=7.3 Hz, 1H). SFC retention time: 33 min. Diastereomer B:¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.44 (br. s., 1H), 8.15 (d,J=8.1 Hz, 1H), 8.11 (br. s., 1H), 7.65 (d, J=7.7 Hz, 2H), 7.49 (d, J=8.1Hz, 1H), 7.32 (t, J=7.3 Hz, 2H), 7.27-7.21 (m, 1H), 5.80 (d, J=11.4 Hz,1H), 4.01 (br. s., 3H), 3.89 (br. s., 1H), 3.74 (d, J=10.3 Hz, 1H), 3.50(d, J=3.3 Hz, 1H), 3.39 (br. s., 1H), 3.26 (t, J=11.7 Hz, 1H), 1.71 (d,J=13.2 Hz, 1H), 1.56 (br. s., 3H), 1.54-1.50 (m, 1H), 1.31 (d, J=8.8 Hz,2H), 1.03 (d, J=13.2 Hz, 1H), 0.51 (br. s., 1H), 0.41 (br. s., 2H), 0.25(br. s., 1H). SFC retention time: 39 min.

Example 4175-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-pyrazole

Step 1: 5-Bromo-2-(4-(methylsulfonyl)phenyl)-3-nitropyridine

Into a mixture of PdCl₂(dppf)-CH₂Cl₂ adduct (0.732 g, 1.00 mmol),potassium phosphate (21.2 g, 100 mmol),(4-(methylsulfonyl)phenyl)boronic acid (10.0 g, 50.0 mmol), and2,5-dibromo-3-nitropyridine (14.1 g, 50.0 mmol) in THF (100 mL) wasbubbled N₂ (g) for 10 min. The pressure bottle was sealed and heated at80° C. in an oil bath for 3 h. The mixture was cooled and poured intowater and EtOAc, then filtered through a layer of Celite. The organiclayer was washed with water and brine, then dried over sodium sulfate toafford a solid, which was washed with Et₂O thoroughly to afford 7.40 g.¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J=2.3 Hz, 1H), 8.43 (d, J=2.0 Hz,1H), 8.10-8.02 (m, 2H), 7.78-7.72 (m, 2H), 3.13 (s, 3H). LC/MS Method 1;RT=1.8 min., M+H=356.

Step 2: 3-Bromo-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole

A 100 mL round bottomed flask was charged with5-bromo-2-(4-(methylsulfonyl)phenyl)-3-nitropyridine (2.00 g, 5.60mmol), triphenylphosphine (3.67 g, 14.0 mmol), and 1,2-dichlorobenzene(50 mL). The flask was placed in an oil bath, the flask was capped witha condenser and heated to 170° C. for 1.5 h. The volatiles were removedunder high vacuum at 70° C., then under a stream of nitrogen for 36 h toafford a black oil. The residue was dissolved in methylene chloride andpurified on a 220 g ISCO column, eluting with 100% methylene chloride to40% EtOAc/methylene chloride over 1800 mL, then 40% EtOAc/methylenechloride to 80% EtOAc/methylene chloride over 1800 mL. Fractions thatcontained the desired product were concentrated to afford 920 mg of alight-tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.66 (d,J=2.0 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.30-8.12(m, 1H), 7.82 (dd, J=8.2, 1.6 Hz, 1H), 3.31 (s, 3H). LC/MS Method 2;RT=0.92 min. M+H=325.

Step 3:(S)-3-Bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

3-Bromo-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole (0.920 g, 2.83 mmol),(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (0.816 g, 4.24 mmol), andtriphenylphosphine (1.11 g, 4.24 mmol) were dissolved in 100 mL of THFand cooled to 0° C. To this was added DIAD (0.825 ml, 4.24 mmol)dropwise via an 18 gauge needle. After 15 min, the ice bath was removed,and the reaction stirred for 1 h longer. The volatiles were removedunder reduced pressure, and the crude material was dissolved inmethylene chloride and purified on an 80 g ISCO column, eluting with 0%EtOAc/methylene chloride to 40% EtOAc/methylene chloride over 800 mL.Fractions containing the product were concentrated to afford 1.52 g as alight-brown solid. LC/MS Method 2 showed a major peak with massesconsistent with the title compound in 32% purity; RT=1.17 min. M+H=499.

Step 4:5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-pyrazole

(S)-3-Bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(80.0 mg, 0.0800 mmol) and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(35.6 mg, 0.160 mmol) were dissolved in 2 mL of DMSO. To this was addedsodium carbonate (25.5 mg, 0.240 mmol) and 0.1 mL of water. Argon wasbubbled through this mixture for 5 min before adding PdCl₂(dppf)-CH₂Cl₂adduct (6.54 mg, 8.01 μmol), and then bubbled in argon while sonicatingfor 30 seconds. The vial was capped and heated in the microwave at 150°C. for 15 min. The crude material was purified via preparative LC/MS(Preparative HPLC Method 1): Fractions containing the desired productwere combined and dried via centrifugal evaporation. The yield of theproduct was 14.1 mg (33%), and its estimated purity by LCMS analysis was98%. Two analytical LC/MS injections were used to determine the finalpurity. Injection 1 conditions LC/MS Method 3; HPLC RT=1.67 min.Injection 2 conditions: LC/MS Method 4; HPLC RT=2.51 min. ¹H NMR (500MHz, DMSO-d₆) δ 8.74 (br. s., 1H), 8.60 (s, 1H), 8.48 (d, J=8.4 Hz, 2H),7.96 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.7 Hz, 3H), 7.46 (s,1H), 7.38-7.30 (m, 3H), 7.30-7.21 (m, 1H), 6.03 (d, J=11.0 Hz, 1H),3.95-3.86 (m, 2H), 3.73 (d, J=8.4 Hz, 1H), 3.57-3.43 (m, 2H), 3.37 (br.s., 1H), 3.27 (t, J=12.1 Hz, 1H), 2.90 (s, 3H), 2.74 (s, 3H), 2.03 (s,3H), 1.81-1.69 (m, 1H), 1.68-1.54 (m, 1H), 1.45-1.28 (m, 1H).

Example 4185-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1-methyl-1H-pyrazole

(S)-3-Bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(40.0 mg, 0.0400 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(16.7 mg, 0.0800 mmol) were dissolved in 2 mL of DMSO. To this was addedsodium carbonate (12.7 mg, 0.120 mmol) and 0.1 mL of water. Argon wasbubbled through the reaction mixture for 5 min while sonicating. To thiswas added PdCl₂(dppf)-CH₂Cl₂ adduct (3.27 mg, 4.00 μmol) and bubbled inargon while sonicating for 30 seconds. The vial was and heated in themicrowave at 150° C. for 15 min. Reaction was filtered and purified viapreparative LC/MS (Preparative HPLC Method 2). Fractions containing thedesired product were combined and dried via centrifugal evaporation. Theyield of the product was 3.10 mg (16%), and its estimated purity by LCMSanalysis was 100%. Two analytical LC/MS injections were used todetermine the final purity. Injection 1 conditions: LC/MS Method 3; HPLCRT=1.54 min. Injection 2 conditions: LC/MS Method 4; HPLC RT=2.48 min.¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.55 (br. s., 1H), 8.47 (d,J=8.1 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.70 (d, J=7.7 Hz, 2H), 7.60 (s,1H), 7.40-7.32 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 6.64 (s, 1H), 6.03 (d,J=11.0 Hz, 1H), 3.91 (br. s., 3H), 3.72 (d, J=10.3 Hz, 1H), 3.56-3.45(m, 2H), 3.35 (d, J=5.5 Hz, 3H), 3.26 (t, J=11.4 Hz, 1H), 1.80-1.69 (m,1H), 1.63 (d, J=9.5 Hz, 1H), 1.37 (d, J=12.5 Hz, 1H).

Example 4191-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]cyclopropan-1-ol

Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate

A 24/40-500 ml, round bottom flask was charged with2,5-dibromo-3-nitropyridine (8.07 g, 28.6 mmol),4-methoxycarbonylphenylboronic acid (4.97 g, 27.6 mmol), THF (143 mL),1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.05 g, 1.43mmol) and potassium phosphate tribasic (2M, 11.6 mL, 23.1 mmol). Theflask was sealed with a rubber septum, and the reaction mixture wasdegassed using ultra pure argon and sonicated for 5 min. The flask wastransferred to an oil bath preheated to 65° C. and held there for 4 h.The mixture was quenched with water, diluted with ethyl acetate, andfiltered through a pad of Celite. The contents of the flask weretransferred into a reparatory funnel and the layers were separated. Theorganic was washed with water (2×) and brine (2×). The combined aqueouswas back extracted with ethyl acetate, and the aqueous discarded. Thecombined organics were dried with magnesium sulfate, concentrated underreduced pressure, and purified by silica gel column chromatography (80 gISCO RediSep Rf, loaded in/with: DCM and dried, initial waste: 0 mL,fraction size: 9 mL 13×100 mm, and eluted with dichloromethane inhexanes 0% [200 mL], 0-20% [300 mL], 20% [1000 mL], 20-50% [500 mL], 50%[300 mL]) to give 1.39 g (59%). ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J=2.0Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.18-8.11 (m, 2H), 7.66-7.58 (m, 2H),3.96 (s, 3H). Mass found 337 [M+H]⁺.

Step 2: Methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate

A 14/20-100 mL round bottom flask was charged with methyl4-(5-bromo-3-nitropyridin-2-yl)benzoate (6.68 g, 19.81 mmol) and1,2-bis(diphenylphosphino)ethane (9.87 g, 24.8 mmol). The mixture wassuspended in 1,2-dichlorobenzene (20 mL) and the flask was sealed andvented with a balloon full of nitrogen. The flask was placed into an oilbath preheated to 160° C. and held there for 1 h. Upon cooling, thesolution was diluted with ether, causing a brown precipitate to formwhich was removed by filtration and discarded. The supernatant wasconcentrated under reduced pressure and purified by silica gel columnchromatography (80 g ISCO RediSep Rf, loaded in/with: DCM and dried,initial waste: 0 mL, fraction size: 9 mL 13×100 mm, and eluted withdichloromethane in hexanes 0% [200 mL], 0-100% [300 mL], 100% [1500 mL])to give 2.80 g (46%) as a beige solid. ¹H NMR (400 MHz, CDCl₃) δ 8.95(d, J=2.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.18-8.11 (m, 2H), 7.66-7.58(m, 2H), 3.96 (s, 3H). Mass found 305 [M+H]⁺.

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A 40 mL pressure vial was charged with1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (3.90 g, 10.1 mmol)and diluted with DMF (23 mL). To that solution was added methyl3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (2.80 g, 9.18 mmol),copper(I) iodide (0.262 g, 1.38 mmol), triethylamine (2.56 mL, 18.4mmol) and Pd(Ph₃P)₄ (0.636 g, 0.551 mmol). The vial was sealed, and thereaction mixture was degassed using ultra pure argon and sonication for3 min. After which, the vial was placed into a reaction block preheatedto 100° C. After 30 min, the mixture was diluted with ethyl acetate andwater, and the contents of the vial were filtered through a pad ofCelite. The mixture was concentrated under reduced pressure and purifiedby silica gel column chromatography (40 g ISCO RediSep Rf, loadedin/with: DCM and dried, initial waste: 0 mL, fraction size: 9 mL 13×100mm, and eluted with acetone in DCM 0% [100 mL], 0-30% [150 mL], 30% [300mL], 30-60% [500 mL], 60% [200 mL]) to give 1.75 g (59%) as a light-tansolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.61 (d, J=2.0 Hz,1H), 8.35 (dd, J=8.3, 0.5 Hz, 1H), 8.25 (dd, J=1.4, 0.6 Hz, 1H), 8.16(d, J=1.8 Hz, 1H), 7.90 (dd, J=8.2, 1.4 Hz, 1H), 4.02 (s, 3H), 3.93 (s,3H), 2.30 (s, 3H). Mass found 321 [M+H]⁺.

Step 4: (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A 24/40-50 mL round bottom flask was charged with methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate(250 mg, 0.778 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (299mg, 1.56 mmol), and triphenylphosphine (408 mg, 1.56 mmol). The mixturewas suspended in THF (7780 μL) and cooled to 0° C. Di-tert-butylazodicarboxylate (358 mg, 1.56 mmol) was added in 1 portion. After 30min at 0° C., the reaction was warmed to room temperature and thereaction slowly turned to a deep red. After 30 min at room temperature,the reaction mixture was quenched with TFA (300 μL, 3.89 mmol) andstirred for 30 min. The mixture was concentrated under reduced pressure,diluted with ethyl acetate, and neutralized using a 1.5M potassiumphosphate. The contents of the flask were transferred into a separatoryfunnel, and the layers were separated. The organic was washed withbrine, dried over magnesium sulfate, concentrated under reducedpressure, and purified by silica gel column chromatography (24 g ISCORediSep Rf, loaded in/with: DCM and dried, fraction size: 21 mL 16×150mm, and eluted with acetone in dichloromethane 0% [50 mL], 0-20% [200mL], 20% [150 mL], 20-30% [150 mL], 30% [350 mL]). Collected fractionsto give 338 mg (88%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.8 Hz, 1H),8.47 (d, J=8.3 Hz, 1H), 8.10 (dd, J=8.3, 1.3 Hz, 1H), 7.63 (d, J=1.8 Hz,1H), 7.46 (d, J=7.3 Hz, 2H), 7.40-7.29 (m, 3H), 5.63 (d, J=10.5 Hz, 1H),4.11-4.01 (m, 4H), 3.92-3.82 (m, 4H), 3.61-3.51 (m, 1H), 3.41-3.31 (m,1H), 3.12 (q, J=11.3 Hz, 1H), 2.30 (s, 3H), 2.05 (d, J=13.3 Hz, 1H),1.71-1.52 (m, 2H), 1.51-1.37 (m, 1H), 1.09 (d, J=12.3 Hz, 1H). Massfound 495 [M+H]⁺.

Step 5: (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

A 14/20-15 mL round bottom flask was charged with titanium(IV)isopropoxide (29.6 μL, 0.101 mmol) and diluted with THF (1000 μL). Tothat solution was added (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(100 mg, 0.202 mmol). Ethyl magnesium bromide (1.0M in THF, 1210 μL,1.210 mmol) was then added at room temperature. After 20 min, thereaction mixture was quenched with methanol and concentrated underreduced pressure. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 Acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 Acetonitrile: water with 10-mM ammoniumacetate; Gradient: 25-65% B over 15 min, then a 5-min hold at 100% B;Flow: 20 mL/min. The fractions were collected to give 8.3 mg (8.17%). ¹HNMR (500 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.39 (br. s., 1H), 8.12 (d, J=8.4Hz, 1H), 7.95 (br. s., 1H), 7.65 (d, J=7.3 Hz, 2H), 7.36-7.29 (m, 2H),7.27-7.21 (m, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.17 (s, 1H), 5.80 (d, J=11.4Hz, 1H), 4.05-3.94 (m, 3H), 3.89 (d, J=10.6 Hz, 1H), 3.73 (d, J=8.8 Hz,1H), 3.47 (t, J=11.2 Hz, 1H), 3.42-3.31 (m, 1H), 3.26 (t, J=11.0 Hz,1H), 2.34-2.23 (m, 3H), 1.71 (d, J=13.2 Hz, 1H), 1.61-1.50 (m, 1H),1.38-1.08 (m, 5H), 0.99 (d, J=12.5 Hz, 1H). Mass found 494 [M+H].

Example 4201,4-Dimethyl-5-{5-[(S)-oxan-4-yl)phenyl)methyl]-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-3-yl}-1H-1,2,3-triazole

Step 1: 5-Bromo-2-(4-chlorophenyl)-3-nitropyridine

A 24/40-3 neck 500 mL round bottom flask was charged with2,5-dibromo-3-nitropyridine (12.1 g, 42.9 mmol) and(4-chlorophenyl)boronic acid (7.48 g, 47.8 mmol). The mixture wassuspended with THF (150 mL) and potassium phosphate tribasic, (2M, 42.9mL, 86.0 mmol). PdCl₂(dppf) (0.314 g, 0.429 mmol) was added, and theflask was sealed and degassed using sonication and ultra pure argon for5 min. The mixture was heated to 65° C. After 2 h, the contents of theflask was transferred into a 1 L-round bottom flask and concentratedunder reduced pressure. The resulting black slurry was diluted withethyl acetate and water and filtered through a pad of Celite. Thecontents of the flask were transferred to a separatory funnel, and theorganic was washed with brine (3×). The organics were dried withmagnesium sulfate, concentrated under reduced pressure, and purified bysilica gel column chromatography (120 g ISCO RediSep Rf, loaded in/with:DCM and dried, fraction size: 18 mL 16×150 mm, and eluted withdichloromethane in hexanes 0% [300 mL], 0-20% [450 mL], 20% [1503 mL],20-50% [756 mL], 50% [450 mL]). The fractions were collected to 10.8 g(80%). 1H NMR consistent with desired. ¹H NMR (400 MHz, CDCl₃) δ 8.92(d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.53-7.43 (m, 4H). Mass found314 [M+H]⁺.

Step 2: 3-Bromo-7-chloro-5H-pyrido[3,2-b]indole

A 24/40-250 mL round bottom flask was charged with5-bromo-2-(4-chlorophenyl)-3-nitropyridine (8.83 g, 28.2 mmol) and1,2-bis(diphenylphosphino)ethane (22.4 g, 36.6 mmol). The mixture wassuspended in 1,2-dichlorobenzene (60 mL). The flask was sealed andvented into a nitrogen-filled balloon. The reaction vessel was placedinto an oil bath preheated to 160° C. After 2 h, the mixture wasconcentrated under reduced pressure to give a black slurry. The slurrywas suspended in DCM, which gave a grey precipitate that was collectedby filtration to give 1.5 g of product. The supernatant was loaded ontoa column and purified by silica gel column chromatography (80 g ISCORediSep Rf, loaded in/with: DCM and dried, initial waste: 0 mL, fractionsize: 9 mL 13×100 mm, and eluted with dichloromethane in hexanes 0% [200mL], 0-100% [300 mL], 100% [1500 mL]). The fractions were collected andcombined with the product previously collected to give 3.17 g (40%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.75 (br. s., 1H), 8.56 (d, J=2.0 Hz, 1H),8.22 (d, J=2.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H),7.32 (dd, J=8.3, 1.8 Hz, 1H). Mass found 280 [M+H]⁺.

Step 3:7-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole

A 40 mL-pressure vial was charged with1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (5.10 g, 13.2 mmol)and diluted with DMF (16.5 mL). To that solution was added3-bromo-7-chloro-5H-pyrido[3,2-b]indole (1.86 g, 6.61 mmol), copper(I)iodide (0.189 g, 0.991 mmol), triethylamine (1.01 mL, 7.27 mmol), andPd(Ph₃P)₄ (0.229 g, 0.198 mmol), respectively. The vial was sealed anddegassed using sonication and ultra pure argon for 2 min. The vial wasplaced into a reaction block preheated to 100° C. After 45 min, themixture was diluted with ethyl acetate and water and filtered through apad of Celite. The contents of the flask were transferred to aseparatory funnel and further diluted with ethyl acetate and brine. Thelayers were separated, and the organic was washed with water (2×) andbrine (2×). The combined aqueous was extracted with ethyl acetate (2×),and the aqueous discarded. The combined organics were washed with brine(2×), dried with magnesium sulfate, and concentrated under reducedpressure. The residue was suspended in DCM to give a yellow solid, whichwas collected by filtration to give 520 mg of desired product. Thesupernatant was purified by silica gel column chromatography (40 g ISCORediSep Rf, loaded in/with: DCM and dried, initial waste: 38 mL,fraction size: 9 mL 13×100 mm, and eluted with acetone indichloromethane 0% [151 mL], 0-100% [501 mL], 100% [250 mL]). Thefractions were collected and combined with the product previouslycollected to give 1.56 (79%). ¹H NMR (400 MHz, CDCl₃) δ 8.68 (br. s.,1H), 8.53 (d, J=1.8 Hz, 1H), 8.32 (d, J=8.5 Hz, 1H), 7.70 (d, J=2.0 Hz,1H), 7.56 (d, J=1.3 Hz, 1H), 7.37 (dd, J=8.5, 1.8 Hz, 1H), 4.04 (s, 3H),2.39 (s, 3H). Mass found 298 [M+H]⁺.

Step 4:(S)-7-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A 24/40-100 mL round bottom flask was charged with7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole(250 mg, 0.840 mmol), triphenylphosphine (440 mg, 1.68 mmol), and(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (242 mg, 1.26 mmol). Themixture was dissolved in THF (8397 μL) and cooled to 0° C. Di-tert-butylazodicarboxylate (387 mg, 1.68 mmol) was added in one portion. After 15min, the ice bath was removed. After 1 h, the mixture was concentratedunder reduced pressure and purified by silica gel column chromatography(24 g ISCO RediSep Rf, loaded in/with: DCM and dried, initial waste: 0mL, fraction size: 9 mL 13×100 mm, and eluted with acetone indichloromethane 0% [75 mL], 15% [102 mL], 20% [150 mL], 20-60% [402mL]). The fractions were collected to give 286 mg (72%). ¹H NMR (400MHz, CDCl₃) δ 8.46 (d, J=1.8 Hz, 1H), 8.32 (d, J=8.3 Hz, 1H), 7.71 (d,J=1.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.46-7.41 (m, 2H), 7.40-7.30 (m,4H), 5.45 (d, J=10.5 Hz, 1H), 4.06 (dd, J=11.7, 2.9 Hz, 1H), 3.92-3.84(m, 4H), 3.55 (td, J=11.8, 2.0 Hz, 1H), 3.36 (td, J=11.9, 2.0 Hz, 1H),3.14-3.00 (m, 1H), 2.29 (s, 3H), 2.03 (d, J=14.1 Hz, 1H), 1.67-1.53 (m,1H), 1.50-1.34 (m, 1H), 1.10 (d, J=13.3 Hz, 1H). Mass found 472 [M+H]⁺.

Step 5:1,4-Dimethyl-5-{5-[(S)-oxan-4-yl(phenyl)methyl]-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-3-yl}-1H-1,2,3-triazole

A 2-5 mL microwave vial was charged with dioxane (10.1 mL) andtricyclohexylphosphine (20 wt % in toluene, 0.784 mL, 0.503 mmol). Tothat mixture was added(S)-7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(475 mg, 1.01 mmol), cesium carbonate (656 mg, 2.01 mmol), Pd₂(dba)₃(230 mg, 0.252 mmol), and isopropenylboronic acid pinacol ester (338 mg,2.01 mmol). The vial was sealed, and the reaction mixture was degassedusing sonication and ultra pure argon for 2 min. The vial was placedinto an oil bath preheated to 130° C. After 4 h, the mixture was cooledto room temperature and filtered through a pad of Celite, concentratedunder reduced pressure, and purified by silica gel column chromatography(40 g ISCO RediSep Rf, loaded in/with: DCM and dried, initial waste: 0mL, fraction size: 9 mL 13×100 mm, and eluted with acetone indichloromethane 0% [105 mL], 15% [201 mL], 20% [201 mL], 30% [201 mL],30-100% [402 mL]). The fractions were collected to give 390 mg (81%). ¹HNMR (400 MHz, CDCl₃) δ 8.45 (d, J=1.8 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H),7.74 (s, 1H), 7.56 (td, J=4.1, 1.3 Hz, 2H), 7.48-7.42 (m, 2H), 7.40-7.29(m, 3H), 5.57 (s, 1H), 5.28 (t, J=1.4 Hz, 1H), 4.07 (d, J=12.0 Hz, 1H),3.92-3.83 (m, 5H), 3.61-3.51 (m, 1H), 3.41-3.29 (m, 1H), 3.10 (q, J=11.1Hz, 1H), 2.36-2.26 (m, 5H), 2.10-1.99 (m, 1H), 1.71-1.53 (m, 2H),1.50-1.38 (m, 1H), 1.13 (d, J=13.3 Hz, 1H). Mass found 477 [M+H]⁺.

Example 4211-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-one

A 40 mL pressure vial was charged with(S)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indole(200 mg, 0.419 mmol) and dissolved in 1,4-dioxane (4188 μL). To thatstirring solution was added water (4188 μL) followed by sodium periodate(269 mg, 1.26 mmol) and osmium tetroxide 2.5% Wt in t-butanol (500 μL,0.0400 mmol). The reaction mixture was stirred overnight. After 18.5 h,the contents of the vial were transferred into a reparatory funnel, andthe mixture was diluted with DCM and water. The layers were separated,the aqueous was extracted with DCM (2×), and the aqueous discarded. Thecombined organics were dried with magnesium sulfate, concentrated underreduced pressure, and purified by silica gel column chromatography (24 gISCO RediSep Rf, loaded in/with: DCM and dried, initial waste: 12 mL,fraction size: 9 mL 13×100 mm, and eluted with acetone indichloromethane 0% [75 mL], 0-100% [300 mL], 100% [150 mL]). Thefractions were collected fractions to give 112 mg (56%). ¹H NMR (500MHz, DMSO-d₆) δ 8.71 (br. s., 1H), 8.62 (s, 1H), 8.53 (br. s., 1H), 8.34(d, J=8.4 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.70 (d, J=7.7 Hz, 2H),7.37-7.30 (m, 2H), 7.28-7.21 (m, 1H), 6.02 (d, J=11.4 Hz, 1H), 4.01 (s,3H), 3.94-3.85 (m, 1H), 3.72 (d, J=8.4 Hz, 1H), 3.47 (q, J=11.1 Hz, 2H),3.25 (t, J=11.4 Hz, 1H), 2.78 (s, 3H), 2.30 (s, 3H), 1.76-1.70 (m, 1H),1.69-1.55 (m, 1H), 1.43-1.29 (m, 1H), 0.96 (d, J=12.8 Hz, 1H). Massfound 480 [M+H]⁺.

Examples 422 & 4231-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

Step 1:1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

A flame dried 2.0-5.0 microwave vial was charged with1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-one(75.0 mg, 0.156 mmol) and sealed. The vial was evacuated and purged withnitrogen. THF (1 mL) was added and the mixture was cooled to −78° C.Cyclopropylmagnesium bromide 1.0M in 1-methyltetrahydrofuran (0.938 mL,0.938 mmol) was added drop wise turning the solution from a yellow tobrown color. After 15 min, the vial was removed from the ice bath andallowed to warm to room temperature. After 2.5 h, the reaction wasquenched with a saturated solution of aq. ammonium chloride and dilutedwith ethyl acetate. The contents of the flask were transferred to areparatory funnel, and the layers were separated. The organic was washedwith brine, dried with magnesium sulfate, concentrated under reducedpressure, and purified using silica gel flash chromatography (4 g ISCORediSep Rf, loaded in/with: DCM and dried, initial waste: 0 mL, fractionsize: 9 mL 13×100 mm, and eluted with acetone in dichloromethane 0% [51mL], 0-60% [501 mL], 60% [99 mL]). The fractions were collected to givethe desired product as a diastereomeric mixture. The mixture wasseparated by Chiral SFC: Chiral OJ-H prep column, 30×250 mm, 5 mm,Mobile phase: 10% MeOH in CO₂, 150 bar, Temp: 35° C., Flow rate: 70mL/min for 46 min. UV monitored at 270 nm. Injection: 0.75 mL of ˜5mg/mL in MeOH (20 mg purified by stacked injection) to give Enantiomer A(9.10 mg, 17%) and Enantiomer B (10.5 mg, 19%). Enantiomer A: ¹H NMR(400 MHz, METHANOL-d) δ 8.44 (d, J=1.5 Hz, 1H), 8.32-8.21 (m, 2H), 8.12(s, 1H), 7.62 (d, J=7.3 Hz, 2H), 7.53 (dd, J=8.4, 1.1 Hz, 1H), 7.38-7.30(m, 2H), 7.30-7.22 (m, 1H), 5.76 (d, J=11.0 Hz, 1H), 4.00 (s, 4H),3.87-3.78 (m, 1H), 3.65-3.55 (m, 1H), 3.45-3.34 (m, 2H), 2.32 (s, 3H),1.96 (d, J=12.8 Hz, 1H), 1.71-1.55 (m, 4H), 1.49-1.20 (m, 2H), 1.12 (d,J=13.3 Hz, 1H), 0.89 (d, J=7.3 Hz, 1H), 0.53 (t, J=6.8 Hz, 2H),0.50-0.38 (m, 2H). SFC retention time 33.12 min. Mass found 521 [M+H]⁺.Enantiomer B: ¹H NMR (400 MHz, CD₃OD) δ 8.44 (d, J=1.8 Hz, 1H),8.31-8.25 (m, 2H), 8.13 (s, 1H), 7.63 (d, J=7.3 Hz, 2H), 7.56 (dd,J=8.3, 1.3 Hz, 1H), 7.38-7.31 (m, 2H), 7.29-7.23 (m, 1H), 5.76 (d,J=11.0 Hz, 1H), 4.03-3.94 (m, 4H), 3.82 (dd, J=11.4, 2.9 Hz, 1H), 3.59(td, J=11.9, 1.9 Hz, 1H), 3.45-3.34 (m, 2H), 2.32 (s, 3H), 1.95 (d,J=12.8 Hz, 1H), 1.71-1.54 (m, 4H), 1.50-1.33 (m, 2H), 1.12 (d, J=12.8Hz, 1H), 0.96-0.82 (m, 1H), 0.61-0.51 (m, 2H), 0.50-0.38 (m, 2H). SFCretention time 40.02 min. Mass found 521 [M+H]⁺.

Example 4242-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propane-1,2-diol

A 20 mL scintillation vial was charged with1,4-dimethyl-5-{5-[(S)-oxan-4-yl(phenyl)methyl]-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-3-yl}-1H-1,2,3-triazole(100 mg, 0.209 mmol), which was subsequently suspended in n-PrOH (2094μL). To that suspension was added NMO 50% in H₂O (66.3 μL, 0.314 mmol)followed by osmium tetroxide 4% in H₂O (133 μL, 0.0210 mmol). After ˜5min, the reaction mixture became homogenous. After 2.5 h, the volatileswere evaporated using a stream of nitrogen, and the resulting yellow oilwas diluted with ethyl acetate and water and transferred to a reparatoryfunnel where the layers were separated. The organic was washed withwater and brine. The combined aqueous was extracted with ethyl acetate(2×) and the aqueous discarded. The combined organics were dried withmagnesium sulfate, concentrated under reduced pressure, and purified bysilica gel column chromatography (4 g ISCO RediSep Rf, loaded in/with:DCM and dried, initial waste: 0 mL, fraction size: 6 mL 13×100 mm, andeluted with acetone in dichloromethane 0% [30 mL], 0-100% [201 mL], 100%[100 mL]). Collected fractions to give 67.0 mg (63%). ¹H NMR (400 MHz,CDCl₃) δ 8.45 (d, J=1.8 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.01 (s, 1H),7.58 (d, J=1.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 2H), 7.40-7.29 (m, 4H), 5.60(d, J=10.3 Hz, 1H), 4.07 (d, J=8.8 Hz, 1H), 4.01-3.93 (m, 1H), 3.91-3.78(m, 5H), 3.56 (t, J=11.9 Hz, 1H), 3.35 (t, J=11.8 Hz, 1H), 3.10 (d,J=11.0 Hz, 1H), 2.30 (s, 3H), 2.04 (d, J=11.5 Hz, 1H), 1.85-1.77 (m,1H), 1.70 (s, 3H), 1.64 (dd, J=13.4, 4.4 Hz, 1H), 1.49-1.36 (m, 1H),1.12 (d, J=12.8 Hz, 1H). Mass found 512 [M+H].

Example 4271-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-8-carbonyl]-3-methylazetidin-3-ol

Step 1: 2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine

A 24/40-250 ml, round bottom flask was charged with1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (5.00 g, 13.0 mmol)and diluted with DMF (43.2 mL). To that solution was added5-bromo-2-chloropyridin-3-amine (5.37 g, 25.9 mmol), copper (I) iodide(0.370 g, 1.94 mmol), triethylamine (3.61 mL, 25.9 mmol), and finallyPd(Ph₃P)₄ (1.12 g, 0.971 mmol). The flask was sealed and degassed usingultra pure argon and sonication for 5 min. The flask was placed into anoil bath preheated to 100° C. After 15 h, the reaction mixture wascooled and filtered through a pad of Celite. The black liquid wasconcentrated under reduced pressure. The resulting black slurry wasdiluted with DCM and brine and transferred into a separatory funnel. Athick emulsion made it impossible to separate the layers. The mixturewas re-filtered through Celite. The layers were separated and theorganic was washed with brine (2×), dried with magnesium sulfate,concentrated under reduced pressure, and purified by silica gel columnchromatography (80 g ISCO RediSep Rf, loaded in/with: DCM and dried,initial waste: 102 mL, fraction size: 21 mL 16×150 mm, and eluted withacetone in dichloromethane 0% [201 mL], 0-20% [501 mL], 20-50% [1002mL]). The fractions were collected to 898 mg (31%). ¹H NMR (400 MHz,CDCl₃) δ 7.76 (d, J=2.0 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 4.32 (br. s.,2H), 3.97 (s, 3H), 2.33 (s, 3H). Mass found 223 [M+H]⁺.

Step 2: Methyl4-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

A 24/40-100 ml, round bottom flask was charged with2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine (300 mg,1.34 mmol), 4-methoxycarbonylphenylboronic acid (966 mg, 5.37 mmol), andcopper(II) Acetate (609 mg, 3.35 mmol). 6 g of 4 Å molecular sievepowder was added, and the vial was sealed and evacuated and flushed withargon, twice. To that mixture was added CHCl₃ (13.4 mL) followed bypyridine (432 μL, 5.37 mmol). The sealed flask was degassed using oxygenand sonication for 4 min, and the reaction stirred under an atmosphereof oxygen. After 17 h, the reaction mixture was quenched with ammoniumhydroxide (1000 μL, 25.1 mmol) and diluted with chloroform. Celite andsand was added to aid in filtration. The mixture was filtered,concentrated under reduced pressure, and purified by silica gel columnchromatography (12 g ISCO RediSep Rf, loaded in/with: DCM and dried,initial waste: 0 mL, fraction size: 9 mL 13×100 mm, and eluted withacetone in dichloromethane 0% [51 mL], 5% [51 mL], 10% [150 mL], 15%[150 mL], 15-30% [252 mL]). Collected fractions to give 160 mg (33.3%).¹H NMR (400 MHz, CDCl₃) δ 8.10-8.03 (m, 2H), 7.93 (d, J=2.0 Hz, 1H),7.56 (d, J=2.0 Hz, 1H), 7.23-7.18 (m, 2H), 6.48 (s, 1H), 3.99 (s, 3H),3.92 (s, 3H), 2.38-2.31 (m, 3H). Mass found 357 [M+H]⁺.

Step 3: Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-8-carboxylate

A 2.0-5.0 mL microwave vial was charged with methyl4-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate(276 mg, 0.771 mmol) and dissolved in DMA (5 mL). To that solution wasadded sodium acetate trihydrate (0.181 mL, 1.93 mmol) andbis(triphenylphosphine)palladium(II) dichloride (54.1 mg, 0.0770 mmol).The vial was sealed and degassed using ultra pure argon and sonicationfor 2 min. The reaction mixture was placed into a reaction blockpreheated to 110° C. After 30 min, the reaction was cooled, and thecontents of the microwave vial were transferred to a 100 mL round bottomflask, and the DMA was concentrated under reduced pressure to give abrown oil. The contents of the flask were transferred into a separatoryfunnel and diluted with ethyl acetate and a saturated aq. solution ofammonium chloride. The combined organics were washed with brine (2×),dried with magnesium sulfate, concentrated under reduced pressure, andpurified by silica gel column chromatography (12 g ISCO RediSep Rf,loaded in/with: DCM and dried, initial waste: 0 mL, fraction size: 9 mL13×100 mm, and eluted with acetone in dichloromethane 0% [51 mL], 5% [51mL], 10% [150 mL], 15% [150 mL], 15-30% [252 mL], 30-60% [500 mL]). Thefractions were collected to give 165 mg (67%). ¹H NMR (400 MHz, CDCl₃) δ9.20-9.15 (m, 1H), 8.58 (d, J=2.0 Hz, 2H), 8.32 (dd, J=8.7, 1.6 Hz, 1H),7.73 (d, J=2.0 Hz, 1H), 7.63-7.53 (m, 1H), 4.04 (s, 3H), 4.00 (s, 3H),2.40 (s, 3H). Mass found 306 [M+H]⁺.

Step 4: (R)-Phenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate

A 24/40-100 mL round bottom flask was charged with(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (1.07 g, 5.57 mmol) anddissolved in DCM (27.8 mL). To that solution was added triethylamine(2.33 mL, 16.7 mmol), and the mixture was cooled with an ice bath to 0°C. Mesyl chloride (0.651 mL, 8.35 mmol) was added drop wise. The icebath was allowed to expire, and after 2 h the mixture was quenched witha saturated solution of sodium bicarbonate, vigorously stirred, andtransferred into a separatory funnel where the layers were separated.The organic was washed with a saturated aq. solution of sodiumbicarbonate, brine, and dried with magnesium sulfate. The mixture wasconcentrated under reduced pressure several times using diethyl ether toafford 1.51 g (100%). ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.38 (m, 3H),7.38-7.34 (m, 2H), 5.21 (d, J=9.0 Hz, 1H), 4.05 (dd, J=11.7, 3.1 Hz,1H), 3.91 (ddd, J=11.5, 4.4, 1.1 Hz, 1H), 3.38 (td, J=11.9, 2.3 Hz, 1H),3.29 (td, J=11.8, 2.3 Hz, 1H), 2.61 (s, 3H), 2.18-2.05 (m, 1H),2.05-1.96 (m, 1H), 1.60-1.48 (m, 1H), 1.39-1.26 (m, 1H), 1.17-1.10 (m,1H).

Step 5: (S)-Methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-8-carboxylate

A 2-dram pressure vial was charged with methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-8-carboxylate(165 mg, 0.513 mmol) and dissolved in DMF (5135 μL). To that solutionwas added cesium carbonate (1000 mg, 3.08 mmol) followed by(R)-phenyl(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (833 mg,3.08 mmol). The vial was sealed and placed into an oil bath preheated to40° C. After 65 h, the reaction mixture was quenched with water, and thecontents of the vial were transferred to a separatory funnel where itwas diluted with ethyl acetate and a brine solution. The layers wereseparated, and the organic was washed with brine (2×). The combinedaqueous was extracted with ethyl acetate (2×), and the aqueousdiscarded. The combined organics were washed with water, dried withmagnesium sulfate, concentrated under reduced pressure, and purified bysilica gel column chromatography (12 g ISCO RediSep Rf, loaded in/with:DCM and dried, initial waste: 0 mL, fraction size: 9 mL 13×100 mm, andeluted with acetone in dichloromethane 0% [51 mL], 20% [150 mL], 25%[252 mL], 25-100% [150 mL]). The fractions were collected to give 147 mg(58%). ¹H NMR (400 MHz, CDCl₃) δ 9.16 (d, J=1.3 Hz, 1H), 8.52 (d, J=1.8Hz, 1H), 8.36 (dd, J=8.8, 1.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.62 (d,J=1.8 Hz, 1H), 7.45 (d, J=7.0 Hz, 2H), 7.40-7.29 (m, 3H), 5.56 (d,J=10.8 Hz, 1H), 4.09-4.03 (m, 1H), 4.00 (s, 3H), 3.93-3.84 (m, 4H),3.60-3.51 (m, 1H), 3.40-3.31 (m, 1H), 3.10 (d, J=11.0 Hz, 1H), 2.30 (s,3H), 2.09-1.99 (m, 1H), 1.68-1.58 (m, 1H), 1.44-1.35 (m, 1H), 1.10 (d,J=12.8 Hz, 1H). Mass found 496 [M+H]⁺.

Step 6:(S)-3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-8-carboxylicacid

A 24/40-50 mL round bottom flask was charged with (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-8-carboxylate(148 mg, 0.299 mmol) and dissolved in THF (2489 μL) and diluted withwater (498 μL). To that mixture was added potassium hydroxide (50.3 mg,0.896 mmol). The vial was sealed with a rubber septum and placed into anoil bath preheated to 50° C. After 17.5 h, the reaction mixture wasconcentrated under reduced pressure. The mixture was dissolved in 2 mLof water and acidified to a pH of ˜5 using 5N aq. HCl. As the pHapproached the acidic range, a white solid precipitated out. The mixturewas transferred into a reparatory funnel and extracted with ethylacetate (×4), dried with magnesium sulfate, and concentrated underreduced pressure to give 128 mg (89%). ¹H NMR (400 MHz, CDCl₃) δ 9.56(d, J=1.5 Hz, 1H), 8.59 (d, J=1.8 Hz, 1H), 8.43 (dd, J=8.8, 1.8 Hz, 1H),7.81 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H),7.41-7.30 (m, 3H), 5.59 (d, J=11.0 Hz, 1H), 4.10-4.04 (m, 1H), 3.94-3.84(m, 4H), 3.61-3.52 (m, 1H), 3.41-3.32 (m, 1H), 3.12 (d, J=11.3 Hz, 1H),2.32 (s, 3H), 2.06 (s, 1H), 1.70-1.56 (m, 2H), 1.46-1.40 (m, 1H), 1.12(d, J=13.3 Hz, 1H). Mass found 482 [M+H]⁺.

Step 7:1-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-8-carbonyl]-3-methylazetidin-3-ol

A 1-dram vial was charged with(S)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-8-carboxylicacid (20.0 mg, 0.0420 mmol) and dissolved in DMF (500 μL). To thatsolution was added 3-methylazetidin-3-ol hydrochloride (10.3 mg, 0.0830mmol), Hünig's base (14.5 μL, 0.0830 mmol), and HATU (23.7 mg, 0.0620mmol). After 1 h, the mixture was diluted with 800 μL of methanol andpurified by preparative HPLC: Column: Waters XBridge C18 100×30 mm 5 u,Solvents: A: 95% MeCN 5% Water B: 95% Water 5% MeCN Buffer: 10 mmAmmonium Acetate), flow Rate: 30 mL/min, 1 injection. The fractions werecollected to give 9.70 mg (42%). ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d,J=1.5 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 8.11 (dd, J=8.7, 1.6 Hz, 1H),7.79 (d, J=8.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.44 (d, J=7.0 Hz, 2H),7.39-7.30 (m, 3H), 5.54 (d, J=10.5 Hz, 1H), 4.54-4.17 (m, 4H), 4.09-4.02(m, 1H), 3.92-3.83 (m, 4H), 3.59-3.49 (m, 1H), 3.40-3.31 (m, 1H),3.17-3.03 (m, 1H), 2.40 (s, 1H), 2.30 (s, 3H), 2.02 (d, J=13.6 Hz, 1H),1.59 (s, 4H), 1.47-1.34 (m, 1H), 1.12 (d, J=12.0 Hz, 1H). Mass found 550[M+H]⁺.

Example 4285-[8-(3,3-Difluoroazetidine-1-carbonyl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

5-[8-(3,3-Difluoroazetidine-1-carbonyl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole(14.6 mg, 63%) was prepared from 3,3-difluoroazetidine hydrochloridefollowing the procedures analogous to those described in the synthesisof1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-8-carbonyl]-3-methylazetidin-3-ol.¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.56 (s, 1H), 8.25 (br. s.,1H), 8.00-7.92 (m, 1H), 7.69 (d, J=7.3 Hz, 2H), 7.38-7.30 (m, 2H),7.29-7.22 (m, 1H), 5.89 (d, J=11.4 Hz, 1H), 4.02 (br. s., 3H), 3.93-3.85(m, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.51-3.44 (m, 1H), 3.43-3.35 (m, 6H),3.27 (t, J=11.6 Hz, 1H), 2.31 (s, 3H), 1.70 (d, J=12.8 Hz, 1H),1.61-1.49 (m, 1H), 1.37-1.25 (m, 1H), 0.99 (d, J=11.4 Hz, 1H). Massfound 556 [M+H]⁺.

Example 4291-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indole-8-cabonyl]azetidine-3-ol

The title compound was prepared from 3-hydroxyazetidine hydrochloridefollowing the procedures analogous to those described in the synthesisof 1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-8-carbonyl]-3-methylazetidin-3-olto give 20.7 mg (63%). ¹H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.48(s, 1H), 8.22 (br. s., 1H), 7.91 (d, J=6.6 Hz, 1H), 7.69 (d, J=7.3 Hz,2H), 7.37-7.30 (m, 2H), 7.29-7.23 (m, 1H), 5.87 (d, J=11.4 Hz, 1H),4.68-4.47 (m, 2H), 4.32 (br. s., 1H), 4.15 (br. s., 1H), 4.02 (br. s.,3H), 3.93-3.82 (m, 3H), 3.73 (d, J=9.2 Hz, 1H), 3.51-3.43 (m, 1H),3.43-3.36 (m, 2H), 3.27 (t, J=11.6 Hz, 1H), 2.31 (s, 3H), 1.69 (d,J=11.7 Hz, 1H), 1.60-1.49 (m, 1H), 1.31 (d, J=9.2 Hz, 1H), 1.00 (d,J=12.5 Hz, 1H). Mass found 536 [M+H]⁺.

Example 4305-[8-(3-Fluoroazetidine-1-carbonyl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl]-1,4-dimethyl-1H-1,2,3-triazole

The title compound was prepared from 3-fluoroazetidine followingprocedures analogous to those described in the synthesis of1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-8-carbonyl]-3-methylazetidin-3-olto give 17.2 mg (77%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.51(s, 1H), 8.55 (br. s., 1H), 8.24 (br. s., 1H), 7.93 (d, J=8.8 Hz, 1H),7.70 (d, J=7.7 Hz, 2H), 7.38-7.30 (m, 2H), 7.29-7.22 (m, 1H), 5.89 (d,J=11.0 Hz, 1H), 5.58-5.38 (m, 1H), 4.85-4.34 (m, 3H), 4.17 (br. s., 1H),4.03 (s, 3H), 3.94-3.86 (m, 1H), 3.74 (d, J=8.1 Hz, 1H), 3.53-3.40 (m,2H), 3.37-3.23 (m, 1H), 2.31 (s, 3H), 1.70 (d, J=12.5 Hz, 1H), 1.56 (d,J=10.3 Hz, 1H), 1.38-1.20 (d, J=12.5 Hz, 1H). Mass found 538 [M+H]⁺.

Examples 431 & 432(1S)-1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-oland(1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

Step 1: 5-Bromo-2-(4-chloro-3-fluorophenyl)-3-nitropyridine

A 24/40-3 neck 500 mL round bottom flask was charged with2,5-dibromo-3-nitropyridine (12.1 g, 42.9 mmol) and4-chloro-3-fluorophenylboronic acid (7.48 g, 42.9 mmol). The mixture wasdiluted with THF (150 mL) and aq. potassium phosphate tribasic, 2.0M(42.9 mL, 86 mmol). PdCl₂(dppf) (0.314 g, 0.429 mmol) was added, and theflask was sealed and degassed using sonication and ultra pure argon for5 min. The mixture was heated to 65° C. After 2 h, the mixture wasconcentrated under reduced pressure, diluted with ethyl acetate andwater, and filtered through Celite. The contents of the vial weretransferred into a separatory funnel, and the organic was washed withbrine (3×), dried with magnesium sulfate, concentrated under reducedpressure, and purified by silica gel column chromatography (120 g ISCORediSep Rf, loaded in/with: DCM and dried, fraction size: 18 mL 16×150mm, and eluted with dichloromethane in hexanes 0% [300 mL], 0-20% [450mL], 20% [1503 mL], 20-50% [756 mL], 50% [450 mL]). Only fractionscontaining pure mono-couple product were collected and set aside. Theremaining impure fractions were collected, concentrated under reducedpressure, and re-purified by flash chromatography: (80 g ISCO RediSepRf, loaded in/with: DCM and dried, initial waste: collected bythreshold, fraction size: 18 mL 16×150 mm, and eluted withdichloromethane in hexanes 0% [200 mL], 0-20% [300 mL], 20% [1000 mL],20-50% [500 mL], 50% [275 mL]). The fractions were combined to give10.77 g (67%). ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=2.0 Hz, 1H), 8.34(d, J=2.0 Hz, 1H), 7.50 (dd, J=8.2, 7.4 Hz, 1H), 7.41 (dd, J=9.4, 2.1Hz, 1H), 7.26-7.22 (m, 1H). Mass found 331 [M+H]⁺.

Step 2: 3-Bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indole &3-bromo-7-chloro-8-fluoro-5H-pyrido[3,2-b]indole

A 350 mL-wide neck pressure flask was charged with5-bromo-2-(4-chloro-3-fluorophenyl)-3-nitropyridine (10.7 g, 32.5 mmol)and 1,2-bis(diphenylphosphino)ethane (19.4 g, 48.7 mmol). The mixturewas suspended in 1,2-dichlorobenzene (65 mL). The flask was sealed andplaced into an oil bath preheated to 160° C. After 30 min, the mixturewas concentrated under reduced pressure. The resulting solids werediluted with DCM to give a tan solid, which was collected by filtrationto give 3.2 g of the regioisomer mixture. The supernatant wasconcentrated under reduced pressure and purified by flashchromatography: (80 g ISCO RediSep Rf, loaded in/with: DCM and dried,fraction size: 18 mL 16×150 mm, and eluted with dichloromethane inhexanes 0% [200 mL], 0-100% [500 mL], 100% [1500 mL]). The fractionswere collected and combined with the product previously collected. NMRshowed a 1.5:1 ratio of 8F:6F. The mixture was separated by chiral SFC:Chiralpak IB prep column, 30×250 mm, 5 μm. Mobile phase: 10% MeOH inCO₂, 150 bar. Temp: 35° C. Flow rate: 70 mL/min. for 10 min. UVmonitored at 316 nm. Injection: 1.25 mL of ˜20 mg/mL in 1:1:1DMSO:MeOH:CHCl₃ (4.9 g purified by stacked injection). Regioisomer 1:3-bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indole (1.69 g, 5.64 mmol,17%) was isolated as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d,J=1.8 Hz, 1H), 8.30 (br. s., 1H), 8.02 (d, J=8.5 Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.33 (dd, J=8.5, 6.3 Hz, 1H). SFC retention time: 15.4 min.Mass found 300 [M+H]⁺. Regioisomer 2:3-bromo-7-chloro-8-fluoro-5H-pyrido[3,2-b]indole (2.51 g, 8.38 mmol,25.8%) was isolated as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d,J=1.8 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.91 (d, J=1.8 Hz, 1H), 7.53 (d,J=5.8 Hz, 1H). SFC retention time: 19.67 min. Mass found 300 [M+H]⁺.

Step 3:(S)-3-Bromo-7-chloro-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A 24/40-250 mL round bottom flask was charged with triphenylphosphine(2.63 g, 10.0 mmol) and THF (30 mL) and placed into an ice bath. Asolution of di-tert-butyl azodicarboxylate (2.31 g, 10.0 mmol) dissolvedin THF (5 mL) was added drop wise, and the mixture was stirred. After 30min, (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (1.93 g, 10.0 mmol)was added in one portion, and the mixture was let stir for 30 min.3-Bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indole (1.50 g, 5.01 mmol) wasadded in small portions over the course of 20 min at 0° C. After 15 min,the ice bath was removed. After 1 h, TFA (3.86 mL, 50.1 mmol) was added,and the mixture was let stir for 30 min and concentrated under reducedpressure. The mixture was diluted with ethyl acetate, and the contentsof the flask were transferred into a separatory funnel where the organicwas neutralized with a 1.5M aq. potassium phosphate solution. The layerswere separated, and the organics washed with brine (2×), dried overmagnesium sulfate, concentrated under reduced pressure, and purified bysilica gel column chromatography (80 g ISCO RediSep Rf, loaded in/with:DCM and dried, initial waste: 0 mL, fraction size: 21 mL 16×150 mm, andeluted with dichloromethane in hexanes 0% [150 mL], 0-100% [500 mL],100% [1000 mL], 2% ethyl acetate in DCM [500 mL]). The fractions werecollected to give 1.97 g (83%). ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H),8.03 (d, J=7.8 Hz, 1H), 7.94 (br. s., 1H), 7.55-7.43 (m, 2H), 7.41-7.28(m, 4H), 5.92 (br. s., 1H), 4.10-3.99 (m, 1H), 3.95-3.83 (m, 1H), 3.56(td, J=11.9, 2.1 Hz, 1H), 3.46-3.34 (m, 1H), 3.06 (br. s., 1H), 1.98 (d,J=14.1 Hz, 1H), 1.64-1.37 (m, 2H), 1.01 (d, J=13.6 Hz, 1H). Mass found473 [M+H]⁺.

Step 4:(S)-7-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A 2.0-5.0 mL microwave vial was charged with1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (164 mg, 0.423 mmol)and DMF (3251 μL). To this was added(S)-3-bromo-7-chloro-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(154 mg, 0.325 mmol), triethylamine (49.8 μL, 0.358 mmol), and copper(I)iodide (9.29 mg, 0.0490 mmol). Pd(Ph₃P)₄ (28.2 mg, 0.0240 mmol) wasadded last, and the vial was sealed and degassed using ultra pure argonand sonication for 1 min. The vial was placed into a reaction blockpreheated to 100° C. After 20 min, the reaction was diluted with waterand ethyl acetate and filtered through a pad of Celite to remove theblack emulsion. The filtered solution was transferred into a separatoryfunnel, and the layers were separated. The organics were washed withwater (2×) and brine. The combined aqueous was extracted with ethylacetate, and the aqueous discarded. The combined organics were washedwith brine, dried with magnesium sulfate, concentrated under reducedpressure, and purified by silica gel column chromatography (40 g ISCORediSep Rf, loaded in/with: DCM and dried, initial waste: 0 mL, fractionsize: 18 mL 16×150 mm, and eluted with acetone in dichloromethane 0%[102 mL], 0-20% [150 mL], 20% [300 mL], 20-60% [507 mL], 60% [200 mL]).The fractions were collected to give 1.10 g (89%). ¹H NMR (400 MHz,CDCl₃) δ 8.47 (d, J=1.8 Hz, 1H), 8.12 (dd, J=8.3, 0.5 Hz, 1H), 8.03 (s,1H), 7.49 (d, J=7.3 Hz, 2H), 7.44-7.30 (m, 4H), 6.06 (br. s., 1H),4.10-4.01 (m, 1H), 3.93-3.86 (m, 1H), 3.83 (s, 3H), 3.55 (td, J=11.9,2.0 Hz, 1H), 3.40-3.29 (m, 1H), 3.03 (d, J=11.0 Hz, 1H), 2.05 (d, J=13.6Hz, 1H), 1.70-1.46 (m, 5H), 1.01 (d, J=13.1 Hz, 1H). Mass found 493[M+H]⁺.

Step 5:(5)-1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone

A 10-20 mL microwave vial was charged with tributyl(1-ethoxyvinyl)tin(1.84 mL, 5.79 mmol) and dissolved in dioxane (19.3 mL). To this wasadded(S)-7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(1.89 g, 3.86 mmol), cesium carbonate (2.51 g, 7.71 mmol), Pd2(dba)3(0.265 g, 0.289 mmol), and tricyclohexylphosphine (20 wt % in toluene,0.901 mL, 0.579 mmol). The vial was sealed and degassed using ultra pureargon and sonication for 1 min. The vial was placed into an oil bathpreheated to 130° C. After 15 h, the mixture was cooled to roomtemperature and HCl (3.0N, 12.9 mL, 38.6 mmol) was added. After 30 min,the mixture was filtered through a pad of Celite, quenched with a 1.5Msolution of aq. potassium phosphate and diluted with ethyl acetate. Thecontents of the flask were transferred into a separatory funnel wherethe layers were separated. The organics were washed with a saturatedsolution of sodium bicarbonate, then water and then brine. The combinedorganics were dried with magnesium sulfate, concentrated under reducedpressure, and purified by silica gel column chromatography (24 g ISCORediSep Rf, loaded in/with: DCM and dried, initial waste: 0 mL, fractionsize: 9 mL 13×100 mm, and eluted with acetone in dichloromethane 0% [75mL], 5% [51 mL], 10% [150 mL],10-35% [300 mL], 40% [300 mL]. Thefractions were collected to give 1.34 g (70%). ¹H NMR (400 MHz, CDCl₃) δ8.51 (d, J=1.8 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.84 (dd, J=8.3, 5.8 Hz,1H), 7.60 (br. s., 1H), 7.50 (d, J=7.5 Hz, 2H), 7.43-7.36 (m, 2H), 7.34(d, J=7.0 Hz, 1H), 6.24-6.10 (m, 1H), 4.07 (dd, J=11.9, 2.9 Hz, 1H),3.90 (dd, J=11.8, 2.5 Hz, 1H), 3.83 (s, 3H), 3.57 (td, J=11.9, 1.9 Hz,1H), 3.36 (td, J=11.8, 1.5 Hz, 1H), 3.13-2.99 (m, 1H), 2.85 (d, J=5.3Hz, 3H), 2.26 (s, 3H), 2.10 (d, J=15.6 Hz, 1H), 1.59 (s, 2H), 1.00 (d,J=9.5 Hz, 1H). Mass found 526 [M+H]⁺.

Step 6:(1S)-1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-oland(1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

A 10-20 mL microwave vial was charged with(S)-1-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone(221 mg, 0.444 mmol) and sealed. The vial was evacuated and purged withnitrogen. THF (2961 μL) was added and the mixture cooled to −78° C.Cyclopropylmagnesium bromide (1.0M in 1-methyltetrahydrofuran, 2670 μL,2.66 mmol) was added drop wise. After 15 min, the vial was removed fromthe ice bath and allowed to warm to room temperature. After 2.5 h, thereaction was quenched with a saturated solution of ammonium chloride anddiluted with ethyl acetate. The contents of the flask were transferredto a separatory funnel, and the layers were separated. The organics werewashed with brine, dried with magnesium sulfate, concentrated underreduced pressure, and purified by silica gel column chromatography (12 gISCO RediSep Rf, loaded in/with: DCM and dried, initial waste: 0 mL,fraction size: 9 mL 13×100 mm, and eluted with acetone indichloromethane 0% [75 mL], 0-10% [201 mL], 15% [201 mL], 15-60% [300mL], 60% [150 mL]). The fractions containing both diastereomers werecollected to give 189 mg. The diastereomers were further purified bypreparative HPLC: Column: Waters XBridge C18 100×30 mm 5 u, Solvents: A:95:5 water/Acetonitrile; B: 95:5 Acetonitrile/water; Buffer:10 mmammonium acetate, % B gradient (time): 33% (40 min), Flow Rate: 30mL/min, UV monitored: 254 nm. The diastereomers were separated usingChiral SFC to give Diastereomers A and B: Chiralcel OJ-H prep column,30×250 mm, 5 μm; Mobile phase: 10% MeOH in CO₂, 150 bar; Temp: 35° C.Flow rate: 70 mL/min. for 35 min. UV monitored at 220 nm. Injection:0.25 mL of ˜50 mg/mL in MeOH. Diastereomer A: ¹H NMR (400 MHz, CDCl₃) δ8.42 (s, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.66 (dd, J=7.9, 6.7 Hz, 1H),7.58-7.45 (m, 3H), 7.41-7.28 (m, 3H), 6.16 (br. s., 1H), 4.05 (d, J=9.3Hz, 1H), 3.87 (d, J=9.3 Hz, 1H), 3.80 (s, 3H), 3.56 (t, J=11.2 Hz, 1H),3.40-3.29 (m, 1H), 3.05 (d, J=8.8 Hz, 1H), 2.37 (d, J=18.1 Hz, 1H), 2.24(s, 3H), 2.07 (d, J=13.3 Hz, 1H), 1.80 (s, 3H), 1.71-1.46 (m, 3H), 1.01(d, J=11.8 Hz, 1H), 0.70-0.57 (m, 2H), 0.53 (dd, J=8.2, 5.6 Hz, 2H). SFCretention time: 25 min. HPLC retention time: 25 min. Mass found 539[M+H]⁺. Diastereomer B: ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=1.5 Hz,1H), 8.14 (d, J=8.3 Hz, 1H), 7.67 (dd, J=8.2, 6.7 Hz, 1H), 7.56-7.45 (m,3H), 7.40-7.33 (m, 2H), 7.33-7.28 (m, 1H), 6.17 (br. s., 1H), 4.05 (dd,J=11.5, 2.5 Hz, 1H), 3.89 (dd, J=11.7, 2.4 Hz, 1H), 3.80 (s, 3H), 3.56(td, J=11.8, 1.8 Hz, 1H), 3.40-3.30 (m, 1H), 3.04 (d, J=7.8 Hz, 1H),2.27-2.14 (m, 4H), 2.08 (d, J=13.6 Hz, 1H), 1.81 (s, 3H), 1.70-1.45 (m,3H), 1.03 (d, J=13.1 Hz, 1H), 0.70-0.58 (m, 2H), 0.57-0.45 (m, 2H). SFCretention time 30 min. HPLC retention time: 28 min. Mass found 539[M+H]⁺.

Alternate synthesis of 3-bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indoleStep 1: 5-Bromo-N-(3-chloro-2-fluorophenyl)pyridin-3-amine

A 20 mL microwave vial was charged with 3-chloro-2-fluoroaniline (473μL, 4.22 mmol) and diluted with 1,4-dioxane (16.9 mL). To that solutionwas added 3,5-dibromopyridine (1000 mg, 4.22 mmol), sodium tert-butoxide(568 mg, 5.91 mmol), xantphos (48.9 mg, 0.0840 mmol), andtris(dibenzylideneacetone)dipalladium(0) (38.7 mg, 0.0420 mmol). Thevial was sealed and degassed using ultra pure argon and sonication for 1min. The vial was placed into a reaction block preheated to 80° C. After1 h, the contents of the vial were transferred to a flask, and thevolatiles were concentrated under reduced pressure. The resulting brownsolids were dissolved with ethyl acetate and water. The contents of theflask were transferred into a separatory funnel where the layers wereseparated. The organic was washed with water and brine, dried overmagnesium sulfate, and purified by silica gel flash chromatography. Upondissolving the sample with DCM, a white solid persisted, which wascollected by filtration and washed with hexanes to give 541 mg ofdesired product. The supernatant was concentrated under reduced pressureand purified by silica gel column chromatography (24 g ISCO RediSep Rf,loaded in/with: DCM and dried, initial waste: 0 mL, fraction size: 9 mL13×100 mm, and eluted with ethyl acetate in dichloromethane 0% [75 mL],0-5% [201 mL], 5% [300 mL]). The fractions were collected and combinedwith the previously collected solids to give 921 mg (72%). ¹H NMR (400MHz, CDCl₃) δ 8.35 (d, J=2.5 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 7.58 (t,J=2.1 Hz, 1H), 7.22-7.14 (m, 1H), 7.08-7.01 (m, 2H), 5.86 (br. s., 1H).Mass found 302 [M+H]⁺.

Step 2: 3-Bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indole

A 10-20 mL microwave vial was charged with5-bromo-N-(3-chloro-2-fluorophenyl)pyridin-3-amine (541 mg, 1.79 mmol)and dissolved in TFA (8971 μL). To that solution was added palladium(II) acetate (604 mg, 2.69 mmol). The vial was sealed and placed into anoil bath preheated to 85° C. After 30 min, an additional 200 mg (0.50equiv.) of palladium acetate was added, and the reaction stirred 1 hlonger. After 1 h, the contents of the microwave vial were transferredinto a round bottom flask, and the TFA was concentrated under reducedpressure to give a brown solid. The solids were dissolved with ethylacetate and 35 mL of aqueous ammonia (27-35%) was added and stirred for15 min. The contents of the flask were transferred into a separatoryfunnel, and the layers were separated. The organic was washed with brine(3×) and set aside. The combined aqueous was extracted with ethylacetate (2×), and the aqueous discarded. The combined organics weredried over magnesium sulfate, concentrated under reduced pressure, andpurified by silica gel column chromatography (40 g ISCO RediSep Rf,loaded in/with: DCM and dried, initial waste: 0 mL, fraction size: 21 mL16×150 mm, and eluted with ethyl acetate in dichloromethane 0% [150 mL],0-5% [150 mL], 5% [400 mL]). The fractions containing product werecollected, and the volatiles were removed under reduced pressure to givethe title compound (194 mg, 36%). ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d,J=1.8 Hz, 1H), 8.30 (br. s., 1H), 8.02 (d, J=8.5 Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.33 (dd, J=8.5, 6.3 Hz, 1H). Mass found 299 [M+H]⁺.

Example 433 & Example 434(1S)-1-cyclopropyl-1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-oland(1R)-1-cyclopropyl-1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(5)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol

Diastereomeric mixture1-cyclopropyl-1-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-olwas prepared according to the procedures described for Examples 431 and432 substituting 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole with4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole in Step 4.Separation of the diastereomeric mixture generated in the last step wasperformed using chiral prep SFC to give Diastereomer A and B: ChiralCelOJ-H prep column, 30×250 mm, 5 μm; Mobile phase: 10% MeOH in CO₂, 150bar; Temp: 35° C. Flow rate: 70 mL/min. for 35 min. UV monitored at 220nm. Injection: 0.25 mL of ˜50 mg/mL in MeOH (34 8 mg purified by stackedinjection). Diastereomer A: ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=1.8 Hz,1H), 8.14 (d, J=8.3 Hz, 1H), 7.65 (dd, J=8.3, 6.5 Hz, 1H), 7.54-7.46 (m,3H), 7.40-7.34 (m, 2H), 7.31 (t, J=7.5 Hz, 1H), 6.16 (br. s., 1H), 4.06(d, J=9.0 Hz, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.81 (s, 3H), 3.57 (t,J=10.9 Hz, 1H), 3.41-3.31 (m, 1H), 3.04 (br. s., 1H), 1.80 (s, 3H), 1.27(s, 5H), 1.02 (d, J=13.8 Hz, 1H), 0.69-0.58 (m, 2H), 0.57-0.48 (m, 2H).SFC retention time: 25 min. Mass found 543 [M+H]⁺. Diastereomer B: ¹HNMR (500 MHz, DMSO-d₆) δ 8.54 (br. s., 1H), 8.01 (d, J=8.4 Hz, 1H),7.78-7.06 (m, 7H), 6.00 (br. s., 1H), 4.20-3.82 (m, 4H), 3.77 (d, J=10.3Hz, 1H), 3.49 (t, J=11.4 Hz, 1H), 3.43-3.35 (m, 1H), 3.29 (t, J=11.6 Hz,1H), 1.88-1.46 (m, 6H), 1.35 (d, J=9.9 Hz, 2H), 1.12 (d, J=12.5 Hz, 1H),0.65-0.18 (m, 4H). SFC retention time 30 min. Mass found 543 [M+H]⁺.

Examples 435 & 4361-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

Diastereomeric mixture1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-olwas prepared according to the procedures described for Example 431 and432 substituting (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol for(R)-(2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol in Step 3. Thediastereomers generated in the last step were separated by preparativeHPLC: Column: Waters XBridge C18 100×30 mm 5 u, Solvents: A:95:5water/Acetonitrile; B:95:5 Acetonitrile/water; Buffer:10 mm ammoniumacetate, % B gradient (time): 32% (50 min), Flow Rate: 30 mL/min; 5injections. Diastereomer A: ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.12(d, J=8.3 Hz, 1H), 7.77-7.60 (m, 3H), 7.37-7.29 (m, 1H), 7.26-7.19 (m,1H), 7.06-6.97 (m, 1H), 6.37 (br. s., 1H), 4.10-4.02 (m, 1H), 3.96-3.81(m, 4H), 3.59-3.50 (m, 1H), 3.43-3.29 (m, 2H), 3.17-2.99 (m, 1H),2.43-2.34 (m, 1H), 2.29 (br. s., 3H), 1.97 (d, J=15.3 Hz, 1H), 1.80 (s,3H), 1.59 (s, 1H), 0.97-0.81 (m, 2H), 0.70-0.56 (m, 2H), 0.50 (d, J=6.5Hz, 2H). Mass found 557 [M+H]⁺. HPLC retention time: 39 min.Diastereomer B: ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=8.3 Hz, 1H),7.77-7.60 (m, 3H), 7.36-7.29 (m, 1H), 7.26-7.20 (m, 1H), 7.06-6.98 (m,1H), 6.38 (br. s., 1H), 4.10-4.02 (m, 1H), 3.96-3.81 (m, 4H), 3.60-3.50(m, 1H), 3.42-3.29 (m, 2H), 3.20-2.97 (m, 1H), 2.29 (br. s., 3H),2.08-2.02 (m, 1H), 1.97 (d, J=13.6 Hz, 1H), 1.80 (s, 3H), 1.59 (br. s.,2H), 1.10 (br. s., 1H), 0.95-0.80 (m, 1H), 0.60 (t, J=7.3 Hz, 2H), 0.53(d, J=6.5 Hz, 2H). Mass found 557 [M+H]⁺. HPLC retention time: 44 min.

Example 437 & Example 4381-Cyclopropyl-1-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(2H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol

Diastereomeric mixture1-cyclopropyl-1-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-olwas prepared according to the procedures described for Example 431 and432 substituting (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol for(R)-(2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol in Step 3 and1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole with4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole in Step 4.The diastereomers generated in the last step were separated bypreparative HPLC: Column: Waters XBridge C18 100×30 mm 5 u, Solvents:A:95:5 water/Acetonitrile; B:95:5 Acetonitrile/water; Buffer:10 mmammonium acetate, % B gradient (time): 32% (50 min), Flow Rate: 30mL/min; 5 injections. Diastereomer A: ¹H NMR (500 MHz, DMSO-d₆) δ 8.52(br. s., 1H), 8.30-8.06 (m, 2H), 8.03-7.91 (m, 2H), 7.59 (br. s., 1H),7.32 (d, J=8.1 Hz, 2H), 7.10 (br. s., 1H), 6.30 (br. s., 1H), 4.10 (br.s., 1H), 3.89 (br. s., 4H), 3.78 (d, J=9.9 Hz, 1H), 3.49 (t, J=11.6 Hz,1H), 3.43-3.34 (m, 1H), 3.27 (t, J=11.6 Hz, 1H), 3.17 (br. s., 3H), 1.81(d, J=12.5 Hz, 1H), 1.73 (br. s., 3H), 1.54 (br. s., 1H), 1.39 (br. s.,2H), 1.06 (br. s., 1H). HPLC retention time: 33 min. Diastereomer B: ¹HNMR (500 MHz, DMSO-d₆) δ 8.52 (br. s., 1H), 8.30-8.08 (m, 2H), 8.03-7.92(m, 2H), 7.61 (br. s., 1H), 7.33 (dd, J=15.0, 7.0 Hz, 2H), 7.09 (br. s.,1H), 6.30 (br. s., 1H), 4.07 (br. s., 1H), 3.96-3.83 (m, 4H), 3.78 (d,J=9.9 Hz, 1H), 3.54-3.41 (m, 2H), 3.26 (t, J=11.7 Hz, 1H), 3.17 (br. s.,3H), 1.82 (d, J=12.8 Hz, 1H), 1.72 (br. s., 3H), 1.57-1.29 (m, 3H), 1.04(d, J=11.0 Hz, 1H). HPLC retention time: 36 min. Mass found 557 [M+H]⁺.

Examples 439 & 4401-Cyclopropyl-1-[6-fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

Step 1:(S)-7-Chloro-6-fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A 2.0-5.0 mL microwave vial was charged with4-methoxy-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (156 mg, 0.844mmol) and diluted with NMP (2111 μL).(S)-3-bromo-7-chloro-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(200 mg, 0.422 mmol) was added followed bybis(triphenylphosphine)palladium(II) dichloride (29.6 mg, 0.042 mmol)and tetramethylammonium acetate (112 mg, 0.844 mmol). The vial wassealed and degassed using ultra pure argon and sonication for 1 min. Thevial was placed into a reaction block preheated to 95° C. After 2 h, thereaction was diluted with ethyl acetate and a saturated solution ofsodium bicarbonate. The contents of the vial were transferred into aseparatory funnel where the layers were separated. The organics werewashed with water (2×) and brine, dried with magnesium sulfate,concentrated under reduced pressure, and purified by silica gel columnchromatography (24 g ISCO RediSep Rf, loaded in/with: DCM and dried,initial waste: 0 mL, fraction size: 18 mL 16×150 mm, and eluted withacetone in dichloromethane 0% [75 mL], 0-20% [150 mL], 20% [300 mL],20-60% [300 mL], 60% [200 mL]). Collected fractions to give 218 mg(100%) as a yellow, amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d,J=1.8 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.87 (br. s., 1H), 7.73-7.63 (m,1H), 7.59-7.44 (m, 2H), 7.42-7.29 (m, 3H), 6.01 (br. s., 1H), 4.15 (s,3H), 4.06 (dd, J=11.8, 2.8 Hz, 1H), 3.97 (s, 3H), 3.89 (dd, J=12.0, 2.5Hz, 1H), 3.54 (td, J=11.9, 1.9 Hz, 1H), 3.44-3.31 (m, 1H), 3.14-2.99 (m,1H), 2.09-1.95 (m, 1H), 1.67-1.42 (m, 2H), 1.02 (d, J=12.0 Hz, 1H). Massfound 505 [M+H]⁺.

Step 2:(5)-1-(6-Fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone

Following a procedure analogous to the one described in the synthesis of1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol,(S)-7-chloro-6-fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(218 mg, 0.431 mmol) was converted to(S)-1-(6-fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone(152 mg, 0.296 mmol, 69%). ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=1.8 Hz,1H), 8.18 (d, J=8.0 Hz, 1H), 7.90 (br. s., 1H), 7.72-7.64 (m, 1H),7.59-7.51 (m, 2H), 7.42-7.29 (m, 3H), 6.13 (br. s., 1H), 4.14 (s, 3H),4.07 (dd, J=11.9, 2.4 Hz, 1H), 3.97 (s, 3H), 3.89 (dd, J=11.7, 2.6 Hz,1H), 3.55 (td, J=11.8, 1.8 Hz, 1H), 3.43-3.31 (m, 1H), 3.08 (d, J=7.8Hz, 1H), 2.83 (d, J=5.0 Hz, 3H), 2.04 (d, J=13.1 Hz, 1H), 1.69-1.45 (m,2H), 1.00 (d, J=12.5 Hz, 1H). Mass found 513 [M+H]⁺.

Step 3:1-Cyclopropyl-1-[6-fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

Following a procedure analogous to the one described in the synthesis of1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol,1-cyclopropyl-1-[6-fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol(75 mg, 0.146 mmol) was converted to1-cyclopropyl-1-(6-fluoro-3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-((S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanol.The diastereomers were separated by preparative HPLC: 58 mg dissolved in3 mL of methanol (19 mg/mL), Column: Waters XBridge C18 100×30 mm 5 u,Solvents: A:95:5 water/acetonitrile; B:95:5 acetonitrile/water;Buffer:10 mm ammonium acetate, % B gradient (time): 35% (40 min), FlowRate: 30 mL/min. Diastereomer A: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d,J=1.5 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 7.63 (dd, J=8.3,6.5 Hz, 1H), 7.53 (d, J=7.5 Hz, 2H), 7.41-7.29 (m, 3H), 6.12 (br. s.,1H), 4.14 (s, 3H), 4.06 (dd, J=11.5, 2.3 Hz, 1H), 3.94 (s, 3H), 3.88(dd, J=11.7, 2.4 Hz, 1H), 3.56 (td, J=11.8, 1.8 Hz, 1H), 3.41-3.29 (m,1H), 3.06 (d, J=8.0 Hz, 1H), 2.11-1.98 (m, 2H), 1.79 (s, 3H), 1.71-1.42(m, 2H), 1.03 (d, J=11.8 Hz, 1H), 0.92-0.78 (m, 1H), 0.69-0.58 (m, 2H),0.57-0.45 (m, 2H). HPLC retention time: 33 min. Mass found 555 [M+H]⁺.Diastereomer B: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=1.8 Hz, 1H), 8.11(d, J=8.3 Hz, 1H), 7.81 (s, 1H), 7.62 (dd, J=8.3, 6.5 Hz, 1H), 7.53 (d,J=7.5 Hz, 2H), 7.41-7.28 (m, 3H), 6.11 (br. s., 1H), 4.14 (s, 3H), 4.06(dd, J=11.8, 2.5 Hz, 1H), 3.95 (s, 3H), 3.88 (dd, J=11.8, 2.5 Hz, 1H),3.55 (td, J=11.9, 1.9 Hz, 1H), 3.41-3.28 (m, 1H), 3.06 (d, J=7.8 Hz,1H), 2.14-1.97 (m, 2H), 1.79 (s, 3H), 1.70-1.43 (m, 2H), 1.03 (d, J=12.8Hz, 1H), 0.93-0.79 (m, 1H), 0.69-0.57 (m, 2H), 0.56-0.47 (m, 2H). HPLCretention time: 37 min. Mass found [M+H]⁺.

Example 441 & Example 4422-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]-1,1,1-trifluoropropan-2-ol

(S)-1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone(100 mg, 0.201 mmol) was dissolved in THF (4020 μL). To that solutionwas added (trifluoromethyl)trimethylsilane (297 μL, 2.01 mmol), and themixture was cooled to 0° C. TBAF (1.0 M in THF, 52.5 mg, 0.201 mmol) wasadded drop wise. After 2.5 h, 2 mL of 3N aq. HCl was added. The mixturewas diluted with ethyl acetate and quenched with a 1.5 M aq. potassiumphosphate solution. The contents of the flask were transferred into areparatory funnel where the layers were separated. The organic waswashed with water (2×) and brine (2×), dried with magnesium sulfate,concentrated under reduced pressure, and purified by silica gel columnchromatography (12 g ISCO RediSep Rf, loaded in/with: DCM and dried,initial waste: 0 mL, fraction size: 9 mL 13×100 mm, and eluted withacetone in dichloromethane 0% [75 mL], 0-10% [201 mL], 15% [201 mL],15-60% [300 mL], 60% [150 mL]). The diastereomers were separated bypreparative HPLC: The crude mixture was dissolved in 2.5 mL of methanol.Column: Waters XBridge C18 100×30 mm 5 u, Solvents: A:95:5water/Acetonitrile; B:95:5 Acetonitrile/water; Buffer:10 mm ammoniumacetate, % B gradient (time): 38% (22 min), Flow Rate: 30 mL/min, ˜16mg/mL per injection. Diastereomer A (17.5 mg, 0.0300 mmol, 15%): ¹H NMR(400 MHz, CDCl₃) δ 8.47 (d, J=1.8 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.65(dd, J=8.3, 6.8 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.41-7.29(m, 3H), 6.14 (br. s., 1H), 4.06 (dd, J=11.7, 2.6 Hz, 1H), 3.89 (dd,J=11.8, 2.8 Hz, 1H), 3.82 (s, 3H), 3.56 (td, J=11.9, 1.8 Hz, 1H), 3.47(d, J=6.3 Hz, 1H), 3.34 (td, J=11.9, 1.9 Hz, 1H), 3.10-2.96 (m, 1H),2.25 (s, 3H), 2.13-2.02 (m, 4H), 1.70-1.44 (m, 2H), 1.01 (d, J=12.5 Hz,1H). HPLC retention time: 16 min. Mass found 567 [M+H]⁺. Diastereomer B(19.5 mg, 0.0340 mmol, 17%). ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=1.8Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.68 (dd, J=8.3, 6.8 Hz, 1H), 7.56 (s,1H), 7.48 (d, J=7.3 Hz, 2H), 7.41-7.28 (m, 3H), 6.14 (br. s., 1H), 4.06(dd, J=11.8, 2.5 Hz, 1H), 3.89 (dd, J=11.5, 2.5 Hz, 1H), 3.81 (s, 3H),3.56 (td, J=11.9, 1.9 Hz, 1H), 3.48 (d, J=5.8 Hz, 1H), 3.35 (td, J=11.8,1.8 Hz, 1H), 3.11-2.97 (m, 1H), 2.25 (s, 3H), 2.14-2.02 (m, 4H),1.71-1.42 (m, 2H), 1.00 (d, J=13.1 Hz, 1H). HPLC retention time: 19 min.Mass found 567 [M+H]⁺.

Examples 443 & 4441-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

Step 1:(5)-1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone

1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-olwas prepared according to the procedures described in the synthesis ofExample 431 and 432 by using3-bromo-7-chloro-8-fluoro-5H-pyrido[3,2-b]indole instead of3-bromo-7-chloro-6-fluoro-5H-pyrido[3,2-b]indole. The regioisomers wereseparated at Step 5 by chiral chromatography: Column: Chiralpak OD21×250 mm 10μ, Solvents: A: 0.1% diethylamine/heptane; B: Ethanol, % Bgradient (time): 15% isocratic (50 min), Flow Rate: 15 mL/min; ˜20 mgper injection. Peak 1 was isolated as(S)-1-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone.¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=1.8 Hz, 1H), 8.30 (d, J=5.3 Hz,1H), 8.13 (d, J=10.5 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.46-7.40 (m, 2H),7.39-7.29 (m, 3H), 5.56 (d, J=10.5 Hz, 1H), 4.09-4.02 (m, 1H), 3.90 (s,3H), 3.89-3.82 (m, 1H), 3.59-3.49 (m, 1H), 3.41-3.29 (m, 1H), 3.09 (d,J=11.3 Hz, 1H), 2.82 (d, J=5.8 Hz, 3H), 2.31 (s, 3H), 2.00 (d, J=13.6Hz, 1H), 1.41 (qd, J=12.4, 4.6 Hz, 2H), 1.09 (d, J=12.8 Hz, 1H). Massfound 497 [M+H]⁺.

Step 2:1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(5)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-olwas prepared according to the procedures described in the synthesis of1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol.The diastereomers generated in the last step were separated by ChiralSFC: Chiralpak OJ-H prep column, 30×250 mm, 5 μm. Mobile phase: 20% MeOHin CO₂, 130 bar. Temp: 35° C. Flow rate: 70 mL/min. for 12 min. UVmonitored at 270 nm. Injection: 0.4 mL of ˜10 mg/mL in MeOH (41 mgpurified by stacked injection). Diastereomer A: ¹H NMR (400 MHz, CDCl₃)δ 8.44 (d, J=1.8 Hz, 1H), 8.06-7.97 (m, 2H), 7.57 (d, J=1.8 Hz, 1H),7.43 (d, J=7.0 Hz, 2H), 7.38-7.28 (m, 3H), 5.54 (d, J=10.5 Hz, 1H), 4.06(dd, J=11.8, 2.8 Hz, 1H), 3.93-3.83 (m, 4H), 3.62-3.48 (m, 1H), 3.36(td, J=11.9, 2.1 Hz, 1H), 3.16-2.99 (m, 1H), 2.30 (s, 3H), 2.02 (d,J=13.6 Hz, 1H), 1.94 (d, J=2.3 Hz, 1H), 1.76 (d, J=1.3 Hz, 3H),1.69-1.51 (m, 1H), 1.47-1.35 (m, 1H), 1.14 (d, J=12.0 Hz, 1H), 0.93-0.80(m, 1H), 0.67-0.54 (m, 2H), 0.50-0.42 (m, 2H). SFC retention time: 7.35min. Mass found 539 [M+H]⁺. Diastereomer B: ¹H NMR (400 MHz, CDCl₃) δ8.43 (d, J=1.8 Hz, 1H), 8.07-7.98 (m, 2H), 7.57 (d, J=1.8 Hz, 1H),7.46-7.40 (m, 2H), 7.38-7.29 (m, 3H), 5.54 (d, J=10.3 Hz, 1H), 4.05 (dd,J=11.7, 2.9 Hz, 1H), 3.92-3.84 (m, 4H), 3.59-3.50 (m, 1H), 3.35 (td,J=11.9, 2.1 Hz, 1H), 3.08 (q, J=10.9 Hz, 1H), 2.30 (s, 3H), 2.04-1.94(m, 2H), 1.76 (d, J=1.0 Hz, 3H), 1.68-1.52 (m, 1H), 1.48-1.35 (m, 1H),1.11 (d, J=13.1 Hz, 1H), 0.93-0.81 (m, 1H), 0.69-0.57 (m, 2H), 0.51-0.40(m, 2H). SFC retention time: 9.31 min. Mass found 539 [M+H]⁺.

Examples 445 & 4461-Cyclopropyl-1-{8-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol

1-Cyclopropyl-1-{8-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-olwas prepared according to the procedures described for1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol.In step 3, 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole wasreplaced with4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole. Thediastereomers generated in the last step were separated by Chiral SFC:Chiralcel OJ-H prep column, 30×250 mm, 5 μm. Mobile phase: 20% MeOH inCO₂, 130 bar. Temp: 35° C. Flow rate: 70 mL/min. for 12 min. UVmonitored at 270 nm. Injection: 0.4 mL of ˜10 mg/mL in MeOH (41 mgpurified by stacked injection). Diastereomer A: ¹H NMR (400 MHz, CDCl₃)δ 8.43 (d, J=1.8 Hz, 1H), 8.05-7.98 (m, 2H), 7.58 (d, J=1.8 Hz, 1H),7.43 (d, J=7.3 Hz, 2H), 7.38-7.29 (m, 3H), 5.55 (d, J=10.5 Hz, 1H), 4.06(dd, J=11.8, 3.0 Hz, 1H), 3.93-3.84 (m, 4H), 3.55 (td, J=11.9, 1.8 Hz,1H), 3.36 (td, J=11.9, 1.9 Hz, 1H), 3.08 (q, J=11.0 Hz, 1H), 2.06-1.94(m, 2H), 1.76 (d, J=1.3 Hz, 3H), 1.68-1.50 (m, 1H), 1.48-1.36 (m, 1H),1.13 (d, J=13.1 Hz, 1H), 0.93-0.80 (m, 1H), 0.68-0.55 (m, 2H), 0.51-0.40(m, 2H). SFC retention time: 7.05. Mass found 542 [M+H]⁺. DiastereomerB: ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=1.8 Hz, 1H), 8.06-7.99 (m, 2H),7.57 (d, J=1.8 Hz, 1H), 7.46-7.41 (m, 2H), 7.38-7.29 (m, 3H), 5.55 (d,J=10.5 Hz, 1H), 4.05 (dd, J=11.8, 2.8 Hz, 1H), 3.93-3.84 (m, 4H), 3.54(td, J=11.9, 1.9 Hz, 1H), 3.35 (td, J=11.9, 1.8 Hz, 1H), 3.15-3.01 (m,1H), 2.06-1.96 (m, 2H), 1.76 (d, J=1.0 Hz, 3H), 1.69-1.54 (m, 1H),1.48-1.35 (m, 1H), 1.10 (d, J=12.3 Hz, 1H), 0.89 (t, J=6.8 Hz, 1H),0.69-0.57 (m, 2H), 0.51-0.41 (m, 2H). SFC retention Time: 8.91 min. Massfound 542 [M+H]⁺.

Examples 447 & 4481-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-olwas prepared according to the procedures described for1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol.(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol was replaced for(R)-(2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol. Thediastereomers generated in the last step were separated by ChiralcelOJ-H prep column, 30×250 mm, 5 μm, Mobile phase: 20% MeOH in CO₂, 130bar. Temp: 35° C. Flow rate: 70 mL/min. for 10 min. UV monitored at 270nm. Injection: 0.3 mL of ˜6 mg/mL in 1:1 MeOH:CHCl₃ (35 mg purified bystacked injection). Diastereomer A: ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d,J=1.8 Hz, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.00 (d, J=11.3 Hz, 1H), 7.82 (s,1H), 7.75 (t, J=6.9 Hz, 1H), 7.35-7.29 (m, 1H), 7.25-7.20 (m, 1H),7.08-7.01 (m, 1H), 5.72 (d, J=11.3 Hz, 1H), 4.05 (dd, J=12.0, 3.0 Hz,1H), 4.01 (s, 3H), 3.88 (dd, J=11.9, 2.9 Hz, 1H), 3.57-3.47 (m, 1H),3.38-3.30 (m, 1H), 3.21-3.09 (m, 1H), 2.38 (s, 3H), 1.97 (d, J=3.0 Hz,1H), 1.88 (d, J=12.5 Hz, 1H), 1.76 (d, J=1.3 Hz, 3H), 1.64-1.49 (m, 1H),1.46-1.32 (m, 1H), 1.13 (d, J=13.8 Hz, 1H), 0.88 (d, J=11.3 Hz, 1H),0.67-0.54 (m, 2H), 0.49-0.37 (m, 2H). SFC retention Time: 6.43 min. Massfound 557 [M+H]⁺. Diastereomer B: ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d,J=1.5 Hz, 1H), 8.06 (d, J=6.0 Hz, 1H), 8.00 (d, J=11.5 Hz, 1H), 7.81 (s,1H), 7.74 (t, J=6.8 Hz, 1H), 7.36-7.29 (m, 1H), 7.25-7.20 (m, 1H),7.09-7.02 (m, 1H), 5.72 (d, J=11.5 Hz, 1H), 4.05 (dd, J=11.8, 2.8 Hz,1H), 4.00 (s, 3H), 3.88 (dd, J=11.7, 2.6 Hz, 1H), 3.52 (td, J=11.9, 2.0Hz, 1H), 3.33 (td, J=11.9, 2.0 Hz, 1H), 3.21-3.07 (m, 1H), 2.37 (s, 3H),1.98 (d, J=2.3 Hz, 1H), 1.87 (d, J=13.6 Hz, 1H), 1.76 (d, J=1.3 Hz, 3H),1.66-1.50 (m, 1H), 1.46-1.32 (m, 1H), 1.09 (d, J=12.8 Hz, 1H), 0.95-0.78(m, 1H), 0.69-0.55 (m, 2H), 0.52-0.39 (m, 2H). SFC retention Time: 7.59min. Mass found 557 [M+H]⁺.

Examples 449 & 4501-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

Step 1:2-(4-Chloro-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A dry 24/40-250 mL round bottom flask was charged with5-bromo-2-chloro-1,3-difluorobenzene (5.00 g, 22.0 mmol) and dilutedwith DMSO (44.0 mL). Bis(pinacol)diborane (6.42 g, 25.3 mmol) was addedfollowed by potassium acetate (4.32 g, 44.0 mmol), and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.161 g,0.220 mmol). The flask was sealed and degassed using ultra pure argonand sonication for 5 min. The reaction mixture was placed into an oilbath preheated to 80° C. and vented into a balloon partially filled withnitrogen. After 10 h, the mixture was diluted with ethyl acetate andwater and transferred to a separatory funnel where the organic waswashed with several volumes of water. The combined organics were driedwith magnesium sulfate, concentrated under reduced pressure, andpurified by flash chromatography: (40 g ISCO RediSep Rf, loaded in/with:DCM and dried, initial waste: 0 mL, fraction size: 9 mL 13×100 mm, andeluted with ethyl acetate in hexanes 0% [201 mL], 0-5% [150 mL], 5-10%[252 mL]). Collected fractions to give 3.53 g (59%). ¹H NMR (400 MHz,CDCl₃) δ 7.40-7.35 (m, 2H), 1.35 (s, 12H).

Step 2: 5-Bromo-2-(4-chloro-3,5-difluorophenyl)-3-nitropyridine

A 24/40-100 mL round bottom flask was charged with2,5-dibromo-3-nitropyridine (2.00 g, 7.09 mmol) and2-(4-chloro-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.95 g, 7.09 mmol). The mixture was diluted with THF (30 mL), andPdCl₂(dppf) (0.0520 g, 0.0710 mmol) was added followed by aq. potassiumphosphate tribasic, (2.0 M, 7.09 mL, 14.2 mmol). The vial was sealed anddegassed using ultra pure argon and sonication for 2 min. The vial wasplaced in an oil bath preheated to 65° C. After 35 min, the reactionmixture was concentrated under reduced pressure, diluted with ethylacetate and a brine solution, and filtered through a pad of Celite. Thecontents of the flask were transferred into a separatory funnel, and theorganic was washed with brine (3×) and then back extracted with ethylacetate. The combined organics were dried with magnesium sulfate,concentrated under reduced pressure, and purified by silica gel columnchromatography (40 g ISCO RediSep Rf, loaded in/with: DCM and dried,initial waste: 0 mL, fraction size: 9 mL 13×100 mm, and eluted withdichloromethane in hexanes 0% [102 mL], 0-20% [150 mL], 20% [501 mL],20-50% [252 mL], 50% [150 mL]). The fractions were collected to give1.59 g (64%). ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J=2.0 Hz, 1H), 8.37 (d,J=2.3 Hz, 1H), 7.23-7.16 (m, 2H). Mass found 350 [M+H]⁺.

Step 3: 3-Bromo-7-chloro-6,8-difluoro-5H-pyrido[3,2-b]indole

A 40 mL pressure vial was charged with5-bromo-2-(4-chloro-3,5-difluorophenyl)-3-nitropyridine (1.59 g, 4.55mmol) and 1,2-bis(diphenylphosphino)ethane (2.72 g, 6.82 mmol). Themixture was suspended in 1,2-dichlorobenzene (15 mL), and the vial wassealed and placed into a reaction block preheated to 160° C. After 15min, the contents of the vial were transferred into a 250 mL roundbottom flask and concentrated under reduced pressure. The brown oil waspurified by silica gel column chromatography (24 g ISCO RediSep Rf,loaded in/with: DCM and dried, initial waste: 0 mL, fraction size: 9 mL13×100 mm, and eluted with ethyl acetate in dichloromethane 0% [1500mL]). The fractions were collected to give 722 mg (50%). ¹H NMR (400MHz, CD₃OD) δ 8.57 (s, 1H), 8.16 (s, 1H), 7.94 (d, J=8.5 Hz, 1H). Massfound 317 [M+H]⁺.

Step 4:(S)-3-Bromo-7-chloro-6,8-difluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A 24/40-100 mL round bottom flask was charged with3-bromo-7-chloro-6,8-difluoro-5H-pyrido[3,2-b]indole (349 mg, 1.10mmol), triphenylphosphine (432 mg, 1.65 mmol), and(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (317 mg, 1.65 mmol). Themixture was dissolved in THF (22 mL) and cooled to 0° C. DIAD (342 μL,1.65 mmol) was then added drop wise. The ice bath was allowed to expire.After 5 h, the mixture was concentrated under reduced pressure andpurified by silica gel column chromatography (24 g ISCO RediSep Rf,loaded in/with: DCM and dried, initial waste: 0 mL, fraction size: 9 mL13×100 mm, and eluted with dichloromethane in hexanes 0% [75 mL], 0-100%[150 mL], 100% [1002 mL]). The fractions were collected to give 445 mg(82%). ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 7.95 (br. s., 1H), 7.90(dd, J=0.7, 1.6 Hz, 1H), 7.47 (d, J=7.0 Hz, 2H), 7.42-7.29 (m, 3H), 5.82(br. s., 1H), 4.05 (dd, J=11.7, 2.6 Hz, 1H), 3.89 (dd, J=11.9, 2.4 Hz,1H), 3.56 (td, J=11.9, 2.0 Hz, 1H), 3.44-3.35 (m, 1H), 3.02 (br. s.,1H), 1.97 (d, J=11.0 Hz, 1H), 1.59-1.51 (m, 1H), 1.45 (d, J=7.0 Hz, 1H),1.02 (d, J=12.5 Hz, 1H). Mass found 491 [M+H]⁺.

Step 5:(S)-7-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A 2-5 mL microwave vial was charged with(S)-3-bromo-7-chloro-6,8-difluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(150 mg, 0.305 mmol) and dissolved in DMF (3050 μL). To that solutionwas added copper(I) iodide (11.6 mg, 0.0610 mmol), triethylamine (85.0μL, 0.610 mmol) and 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole(141 mg, 0.366 mmol). Pd(Ph₃P)₄ (35.2 mg, 0.0310 mmol) was added last,and the vial was sealed and degassed using ultra pure argon andsonication for 2 min. The vial was placed into a reaction blockpreheated to 100° C. After 30 min, the reaction was diluted with waterand ethyl acetate and filtered through a pad of Celite to remove theblack emulsion. The filtered solution was transferred into a reparatoryfunnel and the layers were separated. The organics were washed withwater (2×) and brine. The combined aqueous was extracted with ethylacetate, and the aqueous discarded. The combined organics were washedwith brine, dried with magnesium sulfate, concentrated under reducedpressure, and purified by silica gel column chromatography (40 g ISCORediSep Rf, loaded in/with: DCM and dried, initial waste: 0 mL, fractionsize: 9 mL 13×100 mm, and eluted with acetone in dichloromethane 0% [99mL], 0-10% [201 mL], 10% [201 mL], 15% [150 mL], 20% [150 mL], 30% [150mL]). The fractions were collected to give 159 mg (103%). ¹H NMR (400MHz, CDCl₃) δ 8.47 (d, J=1.8 Hz, 1H), 7.99 (dd, J=0.7, 1.6 Hz, 1H), 7.58(br. s., 1H), 7.51-7.29 (m, 5H), 6.00 (br. s., 1H), 4.09-4.01 (m, 1H),3.90 (dd, J=11.7, 2.9 Hz, 1H), 3.84 (s, 3H), 3.55 (td, J=11.9, 2.0 Hz,1H), 3.41-3.30 (m, 1H), 3.02 (d, J=8.0 Hz, 1H), 2.27 (s, 3H), 2.08-2.00(m, 1H), 1.67-1.44 (m, 2H), 1.01 (d, J=12.5 Hz, 1H). Mass found 508[M+H]⁺.

Step 6:(S)-3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indole

(S)-3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-7-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indolewas synthesized using a procedure analogous to the one described in thesynthesis of1-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-one.¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=1.8 Hz, 1H), 7.88 (dd, J=8.3, 0.8Hz, 1H), 7.56 (s, 1H), 7.49 (d, J=7.3 Hz, 2H), 7.41-7.28 (m, 3H), 6.05(br. s., 1H), 5.61-5.57 (m, 1H), 5.27 (s, 1H), 4.08-4.01 (m, 1H), 3.89(dd, J=11.7, 2.6 Hz, 1H), 3.85-3.78 (m, 3H), 3.54 (td, J=11.9, 1.9 Hz,1H), 3.40-3.30 (m, 1H), 3.12-2.95 (m, 1H), 2.25 (s, 6H), 2.04 (d, J=13.6Hz, 1H), 1.66-1.44 (m, 2H), 1.00 (d, J=12.5 Hz, 1H). Mass found 513[M+H]⁺.

Step 7:(5)-1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanone

(S)-1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)ethanonewas synthesized using a procedure analogous to the one described in1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol.¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=1.8 Hz, 1H), 7.95 (d, J=8.0 Hz,1H), 7.59 (br. s., 1H), 7.50-7.43 (m, 2H), 7.42-7.29 (m, 3H), 6.04 (br.s., 1H), 4.11-4.01 (m, 1H), 3.90 (d, J=8.8 Hz, 1H), 3.84 (s, 3H),3.60-3.48 (m, 1H), 3.35 (t, J=11.0 Hz, 1H), 2.99 (br. s., 1H), 2.78 (s,3H), 2.27 (s, 3H), 2.09-2.01 (m, 1H), 1.65-1.45 (m, 2H), 1.05-0.94 (m,1H). Mass found 515 [M+H]⁺.

Step 8:1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol

1-Cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-olwas synthesized using a procedure analogous to the one described in1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol.The diastereomers were separated by chiral SFC: Column: ChiralCel OJ-H,30×250 mm, 5 μm Mobile Phase: 10% MeOH/90% CO₂ Pressure: 120 bar,Temperature: 35° C. Flow Rate: 70 mL/min UV: 270 nm Injection: 0.75 mL(˜6 mg/mL in MeOH:CHCl₃). Diastereomer A: ¹H NMR (400 MHz, CDCl₃) δ 8.45(s, 1H), 7.96 (d, J=12.0 Hz, 1H), 7.58 (br. s., 1H), 7.52-7.29 (m, 5H),6.09 (br. s., 1H), 4.06 (d, J=8.0 Hz, 1H), 3.91 (d, J=9.0 Hz, 1H), 3.82(br. s., 3H), 3.56 (t, J=10.8 Hz, 1H), 3.42-3.30 (m, 1H), 3.01 (br. s.,1H), 2.25 (br. s., 3H), 2.08 (d, J=13.3 Hz, 1H), 1.89 (br. s., 3H),1.69-1.45 (m, 4H), 1.03-0.94 (m, 1H), 0.93-0.79 (m, 2H), 0.67-0.49 (m,2H). SFC retention time: 30.6 min. Mass found 557 [M+H]⁺. DiastereomerB: ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=1.5 Hz, 1H), 7.88 (dd, J=11.8,1.0 Hz, 1H), 7.53 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.29 (m, 3H), 6.08(br. s., 1H), 4.06 (dd, J=11.5, 2.5 Hz, 1H), 3.90 (dd, J=11.7, 2.4 Hz,1H), 3.81 (s, 3H), 3.56 (td, J=11.9, 1.9 Hz, 1H), 3.35 (t, J=11.0 Hz,1H), 3.09 (dd, J=10.0, 4.0 Hz, 1H), 3.05-2.94 (m, 1H), 2.25 (s, 3H),2.06 (d, J=13.6 Hz, 1H), 1.90 (br. s., 3H), 1.69-1.46 (m, 2H), 1.39-1.18(m, 1H), 1.00 (d, J=13.6 Hz, 1H), 0.94-0.79 (m, 2H), 0.69-0.47 (m, 2H).SFC retention time: 37.1 min. Mass found 557 [M+H]⁺.

Example 4512-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-olwas prepared according to the procedures described for the synthesis of1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-olby substituting cyclopropylmagnesium bromide 1.0 M in2-methyltetrahydrofuran for methyllithium 1.6 M in diethyl ether in Step8. The compound was purified by preparative HPLC: Column: Waters XBridgeC18 100×30 mm 5 u, Solvents: water/Acetonitrile/10 mm ammonium acetate,% B gradient (time): 40% (12 min), Flow Rate: 30 mL/min, 6.8 mg perinjection. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=1.8 Hz, 1H), 7.89 (dd,J=11.8, 1.0 Hz, 1H), 7.53 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.29 (m, 3H),6.09 (br. s., 1H), 4.06 (dd, J=11.7, 2.6 Hz, 1H), 3.90 (dd, J=11.7, 2.9Hz, 1H), 3.81 (s, 3H), 3.55 (td, J=11.9, 2.0 Hz, 1H), 3.40-3.29 (m, 1H),3.21 (d, J=6.5 Hz, 1H), 3.07-2.94 (m, 1H), 2.25 (s, 3H), 2.10-2.02 (m,1H), 1.92 (s, 6H), 1.68-1.43 (m, 2H), 0.96 (d, J=12.0 Hz, 1H). HPLCretention time: 7 min. Mass found 531 [M+H]⁺.

Example 4522-{6,8-Difluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

2-{6,8-Difluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-olwas prepared according to the procedures described for1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6,8-difluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-olby substituting 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole with4-(²H₃)methyl-1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole in Step 5.Also substituting cyclopropylmagnesium bromide 1.0 M in2-methyltetrahydrofuran for methyllithium 1.6 M in diethyl ether in Step8 of the same example. The compound was purified by preparative HPLC:Column: Waters XBridge C18 100×30 mm 5 u, Solvents:water/Acetonitrile/ammonium acetate, % B gradient (time): 37% (25 min),Flow Rate: 30 mL/min, 2×250 μL injections (10.8 mg per injection) ¹H NMR(400 MHz, CDCl₃) δ 8.44 (d, J=1.8 Hz, 1H), 7.89 (dd, J=11.8, 1.0 Hz,1H), 7.53 (s, 1H), 7.46 (d, J=7.5 Hz, 2H), 7.41-7.29 (m, 3H), 6.08 (br.s., 1H), 4.06 (dd, J=11.7, 2.6 Hz, 1H), 3.90 (dd, J=11.7, 2.6 Hz, 1H),3.81 (s, 3H), 3.55 (td, J=11.9, 1.9 Hz, 1H), 3.34 (td, J=11.9, 1.6 Hz,1H), 3.21 (d, J=6.3 Hz, 1H), 3.01 (d, J=7.8 Hz, 1H), 2.11-2.02 (m, 1H),1.92 (br. s., 6H), 1.69-1.45 (m, 2H), 0.96 (d, J=13.3 Hz, 1H). HPLCretention time: 9 min. Mass found 534 [M+H]⁺.

Example 4535-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1-methyl-1H-1,2,3-triazole

Step 1: 5-Bromo-2-(4-(methylsulfonyl)phenyl)-3-nitropyridine

In a pressure bottle, a mixture PdCl₂(dppf)-CH₂Cl₂ adduct (0.732 g, 1.00mmol), potassium phosphate (21.2 g, 100 mmol),(4-(methylsulfonyl)phenyl)boronic acid (10.0 g, 50.0 mmol), and2,5-dibromo-3-nitropyridine (14.1 g, 50.0 mmol) in THF (100 mL) wasbubbled with nitrogen for 10 min. The bottle was sealed and heated at80° C. for 3 h. After cooling, the mixture was diluted with EtOAc andfiltered through a layer of SiO₂. The organic layer was washed withwater and brine, dried over sodium sulfate, and concentrated. Theresulting solid was washed with ether to afford 7.40 g (41%) of a solid.¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J=2.0 Hz, 1H), 8.43 (d, J=2.0 Hz,1H), 8.07 (d,d J=1.6, 8 Hz, 2H), 7.63 (d,d J=1.6, 8 Hz, 2H), 3.14 (s,3H).

Step 2: 3-Bromo-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole

A 100 mL round bottomed flask was charged with5-bromo-2-(4-(methylsulfonyl)phenyl)-3-nitropyridine (2.00 g, 5.60mmol), triphenylphosphine (3.67 g, 14.0 mmol) and 1,2-dichlorobenzene(50 mL). The flask was placed in an oil bath, fitted with a condenser,and heated to 170° C. for 1.5 h. The volatiles were removed on a rotovapunder high vacuum at 70° C., then under a stream of nitrogen for 36 h toafford a black oil. The residue was taken up in methylene chloride andpurified on a 220 g ISCO column, eluting with 100% methylene chloride to40% EtOAc/methylene chloride over 1800 mL, then 40% EtOAc/methylenechloride to 80% EtOAc/methylene chloride over 1800 mL. Fractionscontaining the title compound were concentrated to afford 920 mg of alight tan solid, which was contaminated with triphenylphosphine oxide.LC/MS using LC/MS Method 2 indicated the title compound with HPLCRT=0.93 min and triphenylphosphine oxide with HPLC RT=1.01 min.

Step 3:(S)-3-Bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

3-Bromo-7-(methylsulfonyl)-5H-pyrido[3,2-b]indole (0.92 g, 2.83 mmol),(R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (0.816 g, 4.24 mmol) andtriphenylphosphine (1.11 g, 4.24 mmol) were dissolved in 100 mL of THFand cooled to 0° C. To this was added DIAD (0.825 mL, 4.24 mmol)dropwise via an 18 gauge needle. After 15 min, the ice bath was removed,and the reaction stirred for 1 h. Volatiles were removed on a rotovap.The residue was dissolved in methylene chloride and purified on an 80 gISCO column, eluting with 0% EtOAc/methylene chloride to 40%EtOAc/methylene chloride over 800 mL. Fractions containing the titlecompound were concentrated to afford 1.52 g of a white solid. LC/MSusing LC/MS Method 2 indicated impure product with HPLC RT=1.18 min.

Step 4:(S)-(7-(Methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)boronicacid

A mixture of(S)-3-bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(0.700 g, 1.40 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.427 g,1.68 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.0570 g, 0.0700 mmol), andpotassium acetate (0.275 g, 2.80 mmol) was dissolved in 10 mL ofdioxane. Argon was bubbled through the mixture for 5 min whilesonicating. The vial was capped and heated at 90° C. overnight.Volatiles were removed, and the residue dissolved in EtOAc. The organicswere washed with water and brine, dried over MgSO₄, and concentrated toafford 0.980 g of a brown oil. The oil was dissolved in 11 mL of DMSOand purified by HPLC in 1.5 mL aliquots. Column: Luna 10 u C18; 30×100mm. Method: 10% B to 100% B over 17 min. A=90% water/10% methanol/0.1%TFA. B=10% water/90% methanol/0.1% TFA. Fractions that eluted from 11-12min were collected and concentrated to afford 210 mg of a yellow oil. ¹HNMR (400 MHz, CD₃OD) δ 8.71 (br. s., 1H), 8.60-8.40 (m, 3H), 7.85 (dd,J=8.3, 1.5 Hz, 1H), 7.70-7.58 (m, 2H), 7.42-7.30 (m, 2H), 7.30-7.16 (m,1H), 5.87-5.78 (m, 1H), 4.02 (d, J=15.1 Hz, 1H), 3.81 (d, J=11.0 Hz,1H), 3.64 (t, J=11.5 Hz, 1H), 3.52-3.37 (m, 2H), 3.25-3.20 (m, 3H),1.77-1.58 (m, 1H), 1.04 (d, J=12.0 Hz, 1H). LC/MS Method 2; HPLC RT=0.83min.

Step 5:5-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1-methyl-1H-1,2,3-triazole

(S)-(7-(Methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)boronicacid (30 mg, 0.065 mmol) and 5-bromo-1-methyl-1H-1,2,3-triazole (10.5mg, 0.0650 mmol) were dissolved in 1.5 mL of dioxane and 0.5 mL ofwater. To this was added potassium carbonate (26.8 mg, 0.194 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (3.69 mg, 4.52 μmol) and bubbled in argonwhile sonicating for 5 min. The vial was capped and heated at 100° C.for 1 h. The volatiles were removed. The residue was dissolved in 1.5 mLof DMSO, filtered and purified on preparative HPLC using PreparativeHPLC Method 1, but with a gradient of 20% B-80% B over 20 min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The yield of the product was 6.30 mg (18%), and itsestimated purity by LCMS analysis was 94%. Two analytical LC/MSinjections were used to determine the final purity. Injection 1: LC/MSMethod 3; HPLC RT=1.39 min. Injection 2: LC/MS Method 4; HPLC RT=2.20min. ¹H NMR (400 MHz, DMSO-d₆) δ 8.79-8.68 (m, J=1.5 Hz, 2H), 8.64 (br.s., 1H), 8.48 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 7.86 (dd, J=8.2, 1.4 Hz,1H), 7.69 (d, J=7.3 Hz, 2H), 7.41-7.31 (m, 2H), 7.31-7.23 (m, 1H), 6.01(d, J=11.3 Hz, 1H), 4.12 (s, 3H), 3.94-3.91 (m, 1H), 3.71 (d, J=8.5 Hz,1H), 3.56-3.42 (m, 2H), 3.38 (s, 3H), 2.32 (t, J=1.8 Hz, 1H), 1.74 (d,J=12.5 Hz, 1H), 1.68-1.56 (m, 1H), 1.36 (d, J=8.3 Hz, 1H), 0.91 (d,J=13.8 Hz, 1H).

Example 4545-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-imidazole

(S)-(7-(Methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)boronicacid (30.0 mg, 0.0650 mmol) and 5-bromo-1,4-dimethyl-1H-imidazole (11.3mg, 0.0650 mmol) were dissolved in 1.5 mL of dioxane and 0.5 mL ofwater. To this was added potassium carbonate (26.8 mg, 0.194 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (3.69 mg, 4.52 μmol), and the reaction mixturewas degassed by bubbling in argon while sonicating for 5 min. The vialwas capped and heated at 100° C. for 1 h. The crude material waspurified via preparative LC/MS (Preparative HPLC Method 1) with thefollowing modifications: Gradient 30-70% B over 20 min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The yield of the product was 5.80 mg, and its estimatedpurity by LCMS analysis was 91%. Two analytical LC/MS injections wereused to determine the final purity. Injection 1: LC/MS Method 3, HPLCRT=1.32 min. Injection 2: LC/MS Method 4, HPLC RT=2.32 min. ¹H NMR (500MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.45 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.4 Hz,1H), 7.74 (s, 1H), 7.68 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H),7.30-7.23 (m, 1H), 6.01 (d, J=11.0 Hz, 1H), 3.91-3.84 (m, 1H), 3.73 (d,J=8.1 Hz, 1H), 3.54-3.45 (m, 1H), 3.26 (t, J=11.7 Hz, 1H), 2.17 (s, 3H),1.91 (s, 6H), 1.73 (br. s., 1H), 1.63 (d, J=8.8 Hz, 1H), 1.46-1.28 (m,1H), 0.94 (d, J=11.7 Hz, 1H).

Example 4554-{7-Methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-3-methyl-1H-pyrazole

(S)-(7-(Methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-3-yl)boronicacid (20.0 mg, 0.0430 mmol) and 4-bromo-3-methyl-1H-pyrazole (13.9 mg,0.0860 mmol) were dissolved in 1.5 mL of dioxane and 0.2 mL of water. Tothis was added potassium carbonate (17.9 mg, 0.129 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (2.46 mg, 3.02 μmol), and argon was bubbled inwhile sonicating for 5 min. The vial was capped, heated at 100° C. for50 min, and filtered. The crude material was purified via preparativeLC/MS (Preparative HPLC Method 1) with the following modifications:Gradient 10-50% B over 40 min. Fractions containing the desired productwere combined and dried via centrifugal evaporation. The yield of theproduct was 1.20 mg, and its estimated purity by LCMS analysis was 96%.Two analytical LC/MS injections were used to determine the final purityInjection 1: LC/MS Method 3, HPLC RT=1.83 min. Injection 2: LC/MS Method4, HPLC RT=2.37 min. ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 2H), 8.42 (d,J=8.4 Hz, 1H), 8.27 (br. s., 1H), 8.01 (s, 1H), 7.82 (d, J=8.4 Hz, 1H),7.67 (d, J=7.7 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.27 (t, J=7.3 Hz, 1H),5.99 (d, J=11.0 Hz, 1H), 3.90 (s, 2H), 3.72 (d, J=9.9 Hz, 2H), 3.60 (br.s., 2H), 3.52 (t, J=11.2 Hz, 3H), 3.27 (t, J=11.6 Hz, 1H), 2.43 (s, 3H),1.85-1.73 (m, 1H), 1.72-1.58 (m, 1H), 1.46-1.27 (m, 1H), 0.89 (d, J=12.1Hz, 1H).

Examples 456-459

The compounds in Table 15 were prepared from commercially available orpreviously described starting materials according to analogousprocedures described for2-{5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-olor2-{6-fluoro-3-[4-(²H₃)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol.All compounds are homochiral:

TABLE 15 HPLC RT HPLC MS Example Structure (min) Method (M + H) 456Enantiomer A

9.07 A 570.3 457 Enantiomer B

55.05 B 534.6 458 Enantiomer B

6.73 C 536.3 459 Enantiomer A

10.06 D 536.2HPLC Conditions for Table 15: Method A: Column: Chiralcel OJ-Hpreparative column, 30×250 mm, 5 μm; Mobile Phase: 10% methanol in CO₂,150 Bar; Flow: 70 mL/min. Method B: Column: Chiralpak OJ 21×250 mm 10μm; Mobile Phase: 12:88 ethanol:heptane with 0.1% diethylamine; Flow: 15mL/min. Method C: Column: Chiralcel OJ-H preparative column, 30×250 mm,5 μm; Mobile Phase: 15% methanol in CO₂, 150 Bar; Flow: 70 mL/min.Method D: Column: Chiralpak OD 21×250 mm 10 μm; Mobile Phase: 25:75ethanol:heptane with 0.1% diethylamine; Flow: 15 mL/min.

Example 4603-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxamide

Step 1:(S)-3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylicacid

To a solution of (S)-methyl3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate(see Step 2 of Example 70) (330 mg, 0.643 mmol) in THF (7 mL) was addeda solution of potassium hydroxide (124 mg, 1.928 mmol) in water (1.4mL). The reaction was stirred at 50° C. overnight. The reaction wasconcentrated to remove the THF. The reaction was diluted with water andextracted with EtOAc (which was discarded). The aqueous was acidified topH 5 which gave a precipitate. The mixture was extracted with ethylacetate, washed with brine, dried over magnesium sulfate, andconcentrated to give 274 mg (85%) which was used without purification.LCMS (M+H)=500.4.

Step 2:3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole-7-carboxamide

To a solution of(S)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylicacid (10.0 mg, 0.020 mmol) in CH₂Cl₂ (0.5 mL) was added CDI (2.82 mg,0.020 mmol). After stirring for 1 h at room temperature, saturatedammonium hydroxide (0.03 mL) was added and stirring continued overnight.The reaction was concentrated and purified by Prep HPLC (Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 20-60% B over 15 min, then a5-min hold at 100% B; Flow: 20 mL/min) to give 8.3 mg (83%). LCMS:RT=1.58 min; MS (ES): m/z=499.1 [M+H]⁺ (Column: Waters Acquity UPLC BEHC18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow: 1.0mL/min; Detection: UV at 220 nm); HPLC RT=1.37 min (Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow: 1.0mL/min; Detection: UV at 220 nm)

Example 4612-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine

Step 1:(S)-7-(2-Azidopropan-2-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole

A solution of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol-EnantiomerA (Example 70) (250 mg, 0.487 mmol) in DCM (6 mL) was cooled to 0° C.and treated with trimethylsilylazide (0.162 mL, 1.217 mmol). After 5min, BF₃.OEt₂ (0.308 mL, 2.434 mmol) was added and the mixture stirredfor 20 min. The ice bath was removed and the reaction stirred overnight.The mixture was diluted with water and saturated aqueous bicarbonate,and extracted with ethyl acetate. The organics were washed with brine,dried over MgSO₄, filtered, and concentrated to give 236 mg (90%) whichwas used without purification. LCMS (M+H)=539.4.

Step 2:2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine

To a solution of(S)-7-(2-azidopropan-2-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole(235 mg, 0.436 mmol) in THF (7 mL) was added trimethylphosphine (1M inTHF, 0.873 mL, 0.873 mmol) and the resulting solution stirred overnight.The solution was treated with water (0.1 mL) and the reaction stirredovernight. The reaction was concentrated, diluted with EtOAc, and pouredinto water. The organics were washed with water (3×), then brine, driedover MgSO₄, filtered, and concentrated to give 200 mg crude product. Asmall portion of the reaction mixture was purified by Prep HPLC (Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-90% B over40 min, then a 5-min hold at 100% B; Flow: 20 mL/min) to give 10.9 mg(5%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (br. s., 1H), 8.20 (br. s., 1H),8.01 (d, J=8.1 Hz, 1H), 7.72-7.50 (m, 3H), 7.40-7.20 (m, 3H), 5.99 (br.s., 1H), 3.99-3.83 (m, 4H), 3.76 (d, J=8.8 Hz, 1H), 3.50-3.46 (m, 1H),3.28 (t, J=11.9 Hz, 1H), 2.23 (br. s., 3H), 1.89 (s, 6H), 1.80 (d,J=12.1 Hz, 1H), 1.64 (br. s., 3H), 1.35 (d, J=8.4 Hz, 2H), 1.07 (d,J=12.5 Hz, 1H). LCMS (M+H)=513.0.

Example 462N-{2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl)phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}acetamide

To a solution of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine(20 mg, 0.039 mmol) in DCM (1 mL) was added acetyl chloride (0.039 mL,0.039 mmol) and triethylamine (5.44 μl, 0.039 mmol). After stirring for1 h at room temperature, the reaction was concentrated and purified byPrep HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-90% Bover 35 min, then a 5-min hold at 100% B; Flow: 20 mL/min) to give 8.6mg (39%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (br. s., 1H), 8.39 (br. s.,1H), 8.20 (br. s., 1H), 7.96 (d, J=8.1 Hz, 1H), 7.61 (br. s., 2H),7.38-7.22 (m, 4H), 5.96 (br. s., 1H), 4.02-3.82 (m, 4H), 3.77 (d, J=11.0Hz, 1H), 3.48 (d, J=10.6 Hz, 1H), 3.28 (t, J=11.2 Hz, 1H), 2.23 (br. s.,3H), 1.90 (d, J=12.8 Hz, 4H), 1.77 (br. s., 7H), 1.32 (br. s., 2H), 1.10(d, J=12.8 Hz, 1H). LCMS (M+H)=555.5.

Example 463N-{2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}methanesulfonamide

To a solution of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine(30.0 mg, 0.059 mmol) in DCM (1 mL) was added methanesulfonyl chloride(4.54 μl, 0.059 mmol) and triethylamine (0.016 mL, 0.117 mmol). Afterstirring for 30 min, the reaction was diluted with DCM, filtered toremove solids (which were discarded), and concentrated. The residue waspurified by Prep HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 25-90% B over 35 min, then a 5-min hold at 100% B; Flow: 20mL/min) to give 10.2 mg (28%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (br. s.,1H), 8.23 (br. s., 1H), 8.03 (d, J=8.1 Hz, 1H), 7.79 (br. s., 1H),7.69-7.54 (m, 2H), 7.46 (br. s., 1H), 7.39-7.22 (m, 3H), 5.98 (br. s.,1H), 3.99-3.84 (m, 4H), 3.75 (d, J=12.1 Hz, 1H), 3.55-3.44 (m, 4H), 3.28(t, J=11.2 Hz, 1H), 2.22 (br. s., 3H), 1.86 (br. s., 8H), 1.35 (br. s.,2H), 1.09 (br. s., 1H). LCMS (M+H)=591.4.

Example 464 MethylN-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl}carbamate

To a solution of2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-amine(30.0 mg, 0.059 mmol) in DCM (1 mL) was added methyl chloroformate (4.52μl, 0.059 mmol) and potassium carbonate (8.09 mg, 0.059 mmol). Thereaction was stirred overnight at room temperature. The reaction wasdiluted with DCM, filtered to remove solids (which were discarded) andconcentrated. The resulting residue was purified by Prep HPLC (Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-90% B over20 min, then a 5-min hold at 100% B; Flow: 20 mL/min) to give 10.1 mg(30%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (br. s., 1H), 8.22 (br. s., 1H),7.98 (d, J=8.1 Hz, 1H), 7.85 (br. s., 1H), 7.62 (br. s., 2H), 7.39-7.21(m, 4H), 5.97 (br. s., 1H), 4.00-3.83 (m, 4H), 3.77 (d, J=8.8 Hz, 1H),3.49-3.39 (m, 4H), 3.29 (t, J=11.2 Hz, 1H), 2.24 (br. s., 3H), 1.77 (br.s., 8H), 1.32 (br. s., 2H), 1.10 (d, J=11.0 Hz, 1H). LCMS (M+H)=571.5.

Evaluation of Biological Activity

Exemplary compounds were tested for inhibition of BRD2, BRD3, BRD4 andBRDT activity. Experimental procedures and results are provided below.

Cloning, Expression, and Purification of Human Bromodomains for ThermalShift Assays (TSA)

Recombinant DNA clones encoding bromodomains of human proteins wereoptimized for E. coli expression, chemically synthesized (GenScript,Piscataway N.J.), and inserted into a modified pET28 expression vectorto construct tobacco vein mottling virus (TVMV) protease cleavableN-terminal hexahistidine fusions. The non-native amino acids(MGSSHHHHHHSSGETVRFQSM) (SEQ ID NO: 1) were immediately followed bybromodomain proteins with the amino acid residue sequences (followed byaccessions referenced from and numbered according to the UniprotKnowledgebase; Uniprot Consortium; www.uniprot.org) as follows:

CECR2(420-543), Q9BXF3-1; FALZ(2917-3037), Q12830-1; GCN5(731-837),Q92830-1; PCAF(715-831), Q92831-1; BRD2(24-472), P25440-1; BRD3(1-434),Q15059-1; BRD4(44-168), BRD4(333-460), BRD4(44-460), 060885-1;BRDT(1-383), Q58F21-1; BAZ1B(1340-1457), Q9UIG0-1; CREBBP(1081-1197),Q92793-1; EP300(1040-1161), Q09472-1; WDR9(1310-1430), Q9NSI6-1;ATAD2(981-1108), Q6PL18-1; BRD1(556-688), O95696-1; BRD7(129-236),Q9NPI1-1; BRD9(134-239), Q9H8M2-1; BRPF1(626-740), P55201-2;ATAD2B(952-1086), Q9ULI0-1; BAZ2B(2054-2168), Q9UIF8-1; SP140L(400-580),Q9H930-4; 5P140(687-862), Q13342-1; TIF1(896-1014), 015164-1;TRIM28(619-805), Q13263-1; BRWD3(1295-1443), Q6R145-1; TAF1(1377-1503),TAF1(1501-1635), P21675-1; TAF1L(1402-1522), TAF1L(1523-1654), Q8IZX4-1;ASH1L(2433-2564), Q9NR48-1; PB1(43-156), PB1(178-291), PB1(388-494),PB1(645-766), PB1(773-917), Q86U86-1; SMARCA2(1367-1511), P51531-1;SMARCA2-2(1367-1493), P51531-2.

The recombinant vectors were transformed into E. coli BL21(DE3). Thetransformed cells were cultured in 1 L terrific broth in 2.5 L ThomsonUltra Yield shaker flasks at 37° C., 230 rpm and, at a cell density ofOD600 nm=1.0, were induced with 0.5 mM IPTG and incubated in the shakerat 20° C. for 16-18 hours. The cell pellets were harvested bysedimentation and lysed by sonication in buffer containing 0.1 mg/mllysozyme. Each sample was clarified by sedimentation, and thesupernatant was loaded onto a HisTrap affinity column (GE HealthcareLife Sciences). The column was washed and then eluted with an imidazolegradient. The peak protein fractions containing the bromodomain proteinwere pooled, concentrated, and the protein was purified further by sizeexclusion chromatography on a Superdex 200 column (GE Healthcare LifeSciences) equilibrated with the final storage buffer (20 mM Tris-HCl pH8.0, 200 mM NaCl, 5% glycerol, 2 mM DTT). The SEC peak fractionscontaining purified protein at 2-5 mg/ml were pooled, and the pool wasdivided into aliquots, flash frozen in liquid nitrogen, and store at−80° C.

Cloning, Expression, and Purification of Biotinylated Human Bromodomainsfor TR-FRET Assays

Recombinant DNA clones encoding bromodomains of human BRD2, BRD3, BRD4and BRDT were optimized for E. coli expression, chemically synthesized(GenScript, Piscataway N.J.), and inserted into a modified pET28expression vector to construct tobacco vein mottling virus (TVMV)protease cleavable N-terminal hexahistidine fusions followed by a sitespecific biotinylation motif recognized by E. coli biotin ligase (BirA).The non-native amino acids (MGSSHHHHHHSSGETVRFQGLNDIFEAQKIEWHEDTGHM)(SEQ ID NO: 2) were immediately followed by bromodomain constructs ofBRD4 with the amino acid residue sequences (followed by the BRD4accession referenced from and numbered according to the UniprotKnowledgebase; Uniprot Consortium; www.uniprot.org) as follows:BRD4(44-168), BRD4(333-460), BRD4(44-460), BRD4(1-477), O60885-1.

Each of the recombinant vectors were co-transformed into E. coli BL21STAR (DE3) together with a plasmid encoding BirA under chloramphenicolselection. The transformed cells were cultured at 37° C. in 2.5 LThomson Ultra Yield shaker flasks containing 1 L M9-CAS medium (Teknova)supplemented with 40 μg/ml kanamycin, 35 μg/ml chloramphenicol, and 100μM biotin. At a cell density corresponding to an OD600 nm=0.6, thecultures were induced with 0.5 mM IPTG and incubated in the shaker foran additional 20 hours at 20° C. The cell pellets were harvested bysedimentation and lysed by sonication in buffer containing 0.1 mg/mllysozyme. Each sample was clarified by sedimentation, and thesupernatant was loaded onto a HisTrap affinity column. The column waswashed and then eluted with an imidazole gradient. The peak proteinfractions containing the bromodomain protein were pooled and incubatedfor 18 hours at 4° C. with purified His-TVMV protease (1:15 mass ratioof TVMV:BRD4 protein). The sample was exchanged into low imidazolebuffer and passed through a HisTrap column to capture the cleavedHis-tag and His-TVMV enzyme. The protein in the HisTrap column flowthrough was further purified and exchanged into the final storage buffer(PBS pH 7.0, 5% Glycerol, 1 mM DTT) by size exclusion chromatography ona Superdex 200 column. To improve purity, the BRD4(1-477) andBRD4(44-460) proteins were subjected to an additional cation exchangechromatography purification step prior to size exclusion chromatography.Essentially quantitative mono-biotinylation (+226 Da) of each proteinwas confirmed by electrospray ionization mass spectrometry analysis onthe final sample. The purified samples were divided into aliquots, flashfrozen in liquid nitrogen, and stored at −80° C.

Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay

The binding of compounds to bromodomain BRD4 (44-168), BRD4 (333-460),and BRD4 (1-477 or 44-460) was assessed using a time resolvedfluorescent resonance energy transfer binding assay (1), that measuresthe binding of a fluorescently labeled probe molecule to the bromodomainprotein. The bromodomain protein, fluorescent probe molecule (either abiotinylated histone peptide or a fluorescently labeled small molecule),and dose-responsed test compound are incubated together to reachthermodynamic equilibrium. In the absence of a test compound, thebromodomain and small molecule are bound, resulting in a highfluorescent signal. In the presence of a sufficient concentration ofinhibitor, this intercation is disrupted resulting in a lost offluorescent resonance energy transfer.

All assay components were dissolved in buffer composition 20 mM Hepes pH7.5, 150 mM NaCl, 5 mM DTT, 0.005% Tween 20, and 100 ug/ml BSA for BRD4(1-477 and 44-460). The final concentrations of the bromodomain proteinsare 1.6 nM BRD4(44-168), 1 nM BRD4(333-460), and 1 nM BRD4(1-477 or44-460), and the fluorescent probe molecule is 100 nM, 50 nM, and 7.5 nMrespectively. All proteins were biotinylated. A streptavidin labeledwith terbium cryptate (Cisbio SA-Tb) was used as detection, andpre-mixed with the bromodomain protein at a final concentration of 0.2nM. In some instances for BRD4 (44-460), anti-His terbium cryptate wasused as a detection. 7.5 nl of dose-responsed test compound or dmsovehicle (0.0375%) was pre-spotted in a black Corning 384 well plate and10 ul each of bromodomain/detection reagent and fluorescent smallmolecule solution were added to the plate, and the reaction incubatedfor 60 min at room temperature. Plates were then read on EnVision platereader, (λex=340 nm, acceptor λEm=520 nm, and donor λEm=615 nm, LANCED400 mirror). Time resolved fluorescence intensity measurements weremade at both emissions, and the ratio of acceptor/donor was calculatedand used for data analysis. All data was normalized to 16 high vehiclewells and 8 low reference control wells, and then a four parameter curvefit was applied:Y=a+((b−a)/(1+(10x/10c)d)Where ‘a’ is the minimum, ‘b’ is the Hill slope, ‘c’ is the IC50, and‘d’ is the maximum. Histone peptide: Purchased from GenScriptH4K5K8K12K16 Biotin-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV (SEQ IDNO: 3)

The fluorescently labeled small molecule used was a BRD4 inhibitor knownin the art

-   -   1. F. Degorce, A. Card, S. Soh, E. Trinquet, G. P. Knapik and B.        Xie, HTRF: A technology tailored for drug discovery—a review of        theoretical aspects and recent applications. Current Chemical        Genomics (2009) 3, 22-32        Thermal Shift Assay

The effect of compound binding on the thermal stability of thebromodomains was measured using a BioRad CFX real time PCR instrument bymonitoring the fluorescence enhancement of an external probe (SYPROorange) as it binds preferentially to the unfolded protein. Theunfolding reactions were carried out in a 384-well plate in a 4 uLvolume with 2-8 uM of bromodomain protein, 1-2% (v/v) DMSO in buffercontaining 10 mM Hepes, pH 7.4, 500 mM NaCl. SYPRO orange dye was addedat a dilution of 1:500. Compound concentrations ranged from 1.6-100 uM.Unfolding reactions were monitored by first equilibrating the instrumentat 25° C. for 2.4 sec, followed by ramping the temperature in 0.5° C.increments from 25 to 95° C. with 60 s equilibration prior to a read ateach temperature. Excitation and emission filters for the SYPRO orangedye were set to FRET with the excitation range from 450-490 nm and theemission range from 560-580 nm. The midpoint temperature was determinedby calculating the inflection point using the second derivative. Theobserved temperature shifts were recorded as the difference between themidpoint between a reference well containing protein with dmso but noligand and a well containing protein with compound.

The thermal shift assay is a biophysical technique that compares thechange in unfolding transition temperature of a protein obtained in thepresence and absence of a ligand (1). Typically, a fluorescent dye isused to monitor the protein unfolding as the protein is heated. Duringthe unfolding process, hydrophobic regions of the protein are exposed,resulting in an increase in the dye binding and an increase influorescence intensity. The midpoint of the protein unfolding transitionis defined as the Tm. A ligand that binds to the protein causes anincrease in the protein thermal stability, thus increasing the Tm,proportionally to both the ligand concentration and its bindingaffinity.

-   -   1. M. W. Pantoliano, E. C. Petrella, J. D. Kwasnoski, V. S.        Lobanov, J. Myslik, E. Graf, T. Carver, E. Asel, B. A.        Springer, P. Lane, F. R. Salemme, High-density miniaturized        thermal shift assays as a general strategy for drug        discovery. J. Biomol. Screen 6(2001) 429-440.    -   2. M. D. Cummings, M. A. Farnum, M. I. Nelen, Universal        screening methods and application of ThermoFluor. J. Biomol.        Screen 11 (2006) 854-863        MYC HCS Assay

Tumor cells in complete RPMI growth media (Gibco, 11875-085)supplemented with 10% FBS were harvested and plated into 384 blackclear-bottom PDL cell culture plates in 30 ul media with 10,000 cellsper well. After compound treatment at 37 C for 4 hrs, cells were fixedin 4% Formaldehyde at room temperature for 30 min and subsequentlypermeabilized. After washing and blocking, the plates were thenincubated with anti-myc primary antibody 1:1000 (Cell SignalingTechnology, 5605) at RT overnight. The following day, cells were washedand blocked before adding secondary antibody Alexa 488 Goat-anti Rabbit1:2000 (Invitrogen, A11034) at RT in the dark for 1 hr. Cells weresubsequently washed and scanned on the Cellomics ArrayScan with 10×objective lens.

MTS Cell Proliferation Assay

Tumor cells were plated at certain seeding densities in 384-well blackclear bottom Matrix plates at 40 ul per well and incubated overnight at37° C. in 5% CO₂ before assaying. On the next day, one set of cellplates (T0 plates) were used to determine time zero cell density, and3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoliumfrom the CellTiter 96 AQueous Non-Radioactive Cell proliferation Kit(Promega, G5440) was added at 4 μl/well into T0 plates followed byincubation at 37° C. in 5% CO₂ for three hours. Absorbance at 490 nm wasmeasured on an Envision reader (Perkin Elmer, Boston, Mass.). On thesame day, the remaining cell plates (T72 plates) were treated withcompounds at 37° C. in 5% CO₂. After 72 hours, 4 ul MTS reagents werethen added onto those cell plates. The plates were further incubated at37° C. in 5% CO₂ for three hours and the absorbance values at A490 weremeasured on an Envision reader.

Human Tumor Xenograft Models in Mice

All rodents were obtained from Jackson Laboratory. (Bar Harbor, Me.),and maintained in an ammonia-free environment in a defined andpathogen-free colony. All mice were quarantined approximately 1 weekprior to their use for tumor propagation and drug efficacy testing. Micewere fed food and water ad libitum. The animal care program ofBristol-Myers Squibb Pharmaceutical Research Institute is fullyaccredited by the American Association for Accreditation of LaboratoryAnimal Care (AAALAC). All experiments were performed in accordance withBristol-Myers Squibb (BMS) animal test methods and guidelines.

Tumor xenografts were grown and maintained subcutaneously (SC) in NSG(NOD scid IL2 receptor gamma chain knockout) mice (Jackson Lab). Tumorswere propagated as subcutaneous transplants using tumor fragmentsobtained from donor mice.

Preclinical Chemotherapy Trials

The required numbers of animals needed to detect a meaningful responsewere pooled at the start of the experiment and each was given bilateralsubcutaneous implants of two tumor fragments (˜20 mg) with a 13-gaugetrocar. Tumors were allowed to grow to the pre-determined size window(tumors outside the range were excluded) and animals were evenlydistributed to various treatment and control groups. There weretypically 6-8 mice per treatment and control groups, consisting of 10-12tumors. Treatment of each animal was based on individual body weight.Treated animals were checked daily for treatment relatedtoxicity/mortality. Each group of animals was weighed before theinitiation of treatment (Wt₁) and then again following the lasttreatment dose (Wt₂). The difference in body weight (Wt₂−Wt₁) provides ameasure of treatment-related toxicity.

Tumor response was determined by measurement of tumors with a calipertwice a week, until the tumors reached a predetermined “target” size of0.5 gm or 1 gm depending on the tumor type. Tumor weights (mg) wereestimated from the formula:Tumor weight=(length×width²)÷2

Tumor response criteria are expressed in terms of tumor growthinhibition (% TGI). Tumor growth delay is defined as the difference intime (days) required for the treated tumors (T) to reach a predeterminedtarget size compared to those of the control group (C). For thispurpose, the tumor weight of a group is expressed as medium tumor weight(MTW).

Tumor growth inhibition is calculated as follows:

${\%\mspace{14mu}{Tumor}\mspace{14mu}{Growth}\mspace{14mu}{Inhibition}} = \frac{( {1 - {\frac{T_{t}}{T_{0}}*\frac{C_{0}}{C_{t}}}} )}{( {1 - \frac{C_{0}}{C_{t}}} )}$where,C_(t)=Median control tumor size at end of treatmentC₀=Median control tumor size at treatment initiationT_(t)=Median tumor size of treated group at end of treatmentT₀=Median tumor size of treated group at treatment initiation

Activity is defined as the achievement of durable tumor growthinhibition of 50% or greater (i.e. TGI≧50%) for a period equivalent toat least 1 tumor volume doubling time and drug treatment must be for aperiod equivalent to at least 2 tumor volume doubling time.

Tumor response was also expressed in terms of tumor growth delay andexpressed as log cell kill (LCK value), defined as the difference intime (days) required for the treated tumors (T) to reach a predeterminedtarget size compared to those of the control group (C).

Whenever possible, antitumor activity was determined at a range of doselevels up to the maximum tolerated dose (MTD) which is defined as thedose level immediately below which excessive toxicity (i.e. more thanone death) occurred. When death occurred, the day of death was recorded.Treated mice dying prior to having their tumors reach target size wereconsidered to have died from drug toxicity. No control mice died bearingtumors less than target size. Treatment groups with more than one deathcaused by drug toxicity were considered to have had excessively toxictreatments and their data were not included in the evaluation of acompound's antitumor efficacy.

Potential drug toxicity interaction affecting treatment tolerability isan important consideration in combination chemotherapy trials.Interpretation of combination therapeutic results must be based oncomparison of antitumor activity of the best possible response for thesingle agents versus the combination at comparably tolerated doses.Therefore, therapeutic synergism was defined as a therapeutic effectachieved with a tolerated regimen of the combined agents that exceededthe optimal effect achieved at any tolerated dose of monotherapy.Statistical evaluations of data were performed using Gehan's generalizedWilcoxon test. Statistical significance was declared at P<0.05.

Drug Administration

For administration of BET inhibitors to rodents, compounds weredissolved in 90% PEG300/10% TPGS/10% Ethanol. BET inhibitors weretypically administered orally on a schedule of QDx7 or QDx10 (5 day-on-2day-off), although other schedules had also been evaluated and shown tobe efficacious

Results:

The following Table shows the results of certain compounds of theinvention against the H187 Human Small Cell Carcinoma and the JJN3Rmultiple myeloma cell line.

Cell Dose Treatment Line (mg/kg) Schedule % TGI LCK 1 H187 15 2QDx7 104.0 1.2 1 H187 5 2QDx7  88.0 1.0 54 H187 10 QDx7 102.0 0.9 54 H187 5QDx7 100.0 0.7 70 H187 10 QDx7 96.0 1.6 70 H187 3 QDx7 90.0 1.0 70 H1871 QDx7 82.0 0.7 203 JJN3R 4 QDx7 105 >1.4 203 JJN3R 1 QDx7 93 0.7 263JJN3R 4 QDx7 52 0.3 263 JJN3R 1 QDx7 6 0.2 267 JJN3R 4 QDx7 67 0.6 267JJN3R 1 QDx7 10 0 276 JJN3R 4 QDx7 95 1 276 JJN3R 1 QDx7 56 0.3 278JJN3R 4 QDx7 110 >1.4 278 JJN3R 1 QDx7 103 1 279 JJN3R 4 QDx7 110 >1.4279 JJN3R 1 QDx7 88 0.6 432 JJN3R 4 QDx7 102 1.4 432 JJN3R 1 QDx7 51 0.4433 JJN3R 1 QDx7 54 0.5 434 JJN3R 1 QDx7 82 0.5 436 JJN3R 4 QDx7 116 0.9436 JJN3R 1 QDx7 71 0.6

The activity data shown below is based on the use of one of the FRETassays described. Compounds with an IC₅₀ less than 1500 nM are shownwith (+), compounds with an IC₅₀ less than 25 nM are shown with (++) andthose with an IC₅₀ less than 5 nM are shown with (+++).

FRET BRD4 Example # IC₅₀ (nM) Example 1 +++ Example 2 +++ Example 3 +++Example 4 ++ Example 5 +++ Example 6 ++ Example 7 ++ Example 8 +++Example 9 +++ Example 10 ++ Example 11 ++ Example 12 ++ Example 13 +++Example 14 ++ Example 15 +++ Example 16 ++ Example 17 ++ Example 18 +Example 19 +++ Example 20 ++ Example 21 +++ Example 22 +++ Example 23+++ Example 24 + Example 25 +++ Example 26 ++ Example 27 +++ Example 28+++ Example 29 +++ Example 30 +++ Example 31 +++ Example 32 +++ Example33 +++ Example 34 +++ Example 35 ++ Example 36 ++ Example 37 +++ Example38 ++ Example 39 + Example 40 ++ Example 41 + Example 42 ++ Example 43 +Example 44 +++ Example 45 +++ Example 46 + Example 47 ++ Example 48 ++Example 49 +++ Example 50 + Example 51 + Example 52 ++ Example 53 +Example 54 +++ Example 55 +++ Example 56 +++ Example 57 +++ Example 58+++ Example 59 +++ Example 60 +++ Example 61 +++ Example 62 ++ Example63 ++ Example 64 +++ Example 65 +++ Example 66 +++ Example 67 ++ Example69 +++ Example 70 +++ Example 71 +++ Example 72 ++ Example 73 +++Example 74 ++ Example 75 +++ Example 76 +++ Example 77 +++ Example 78+++ Example 79 ++ Example 80 ++ Example 81 +++ Example 82 ++ Example 83++ Example 84 + Example 85 + Example 86 +++ Example 87 + Example 88 +++Example 89 ++ Example 90 +++ Example 91 ++ Example 92 +++ Example 93 +++Example 94 +++ Example 95 +++ Example 96 ++ Example 97 +++ Example 98+++ Example 99 +++ Example 100 +++ Example 101 ++ Example 102 +++Example 103 +++ Example 104 +++ Example 105 +++ Example 106 +++ Example107 +++ Example 108 +++ Example 109 +++ Example 110 +++ Example 111 +++Example 112 +++ Example 113 + Example 114 +++ Example 115 +++ Example116 ++ Example 117 +++ Example 118 +++ Example 119 +++ Example 120 +++Example 121 ++ Example 122 +++ Example 123 +++ Example 124 +++ Example125 +++ Example 126 ++ Example 127 +++ Example 128 ++ Example 129 +Example 130 +++ Example 131 +++ Example 132 +++ Example 133 +++ Example134 +++ Example 135 +++ Example 136 +++ Example 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What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.2. A pharmaceutical composition which comprises a compound according toclaim 1 or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers, diluents or excipients.
 3. Amethod of treating cancer comprising administering a therapeuticallyeffective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof wherein the cancer is smallcell lung cancer, non-small cell lung cancer, colorectal cancer,multiple myeloma or AML.